Sulfonamides as modulators of sodium channels

ABSTRACT

The invention relates to compounds of formula I or pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels: (I). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders, including pain.

TECHNICAL FIELD OF THE INVENTION

The invention relates to compounds useful as inhibitors of sodiumchannels. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders includingpain.

BACKGROUND OF THE INVENTION

Pain is a protective mechanism that allows healthy animals to avoidtissue damage and to prevent further damage to injured tissue.Nonetheless there are many conditions where pain persists beyond itsusefulness, or where patients would benefit from inhibition of pain.Neuropathic pain is a form of chronic pain caused by an injury to thesensory nerves (Dieleman, J. P., et al., Incidence rates and treatmentof neuropathic pain conditions in the general population. Pain, 2008.137(3): p. 681-8). Neuropathic pain can be divided into two categories,pain caused by generalized metabolic damage to the nerve and pain causedby a discrete nerve injury. The metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy.Discrete nerve injuries indications include post amputation pain,post-surgical nerve injury pain, and nerve entrapment injuries likeneuropathic back pain.

Voltage-gated sodium channels (Na_(v)'s) play a critical role in painsignaling. Na_(v)'s are key biological mediators of electrical signalingas they are the primary mediators of the rapid upstroke of the actionpotential of many excitable cell types (e.g. neurons, skeletal myocytes,cardiac myocytes). The evidence for the role of these channels in normalphysiology, the pathological states arising from mutations in sodiumchannel genes, preclinical work in animal models, and the clinicalpharmacology of known sodium channel modulating agents all point to thecentral role of Na_(v)'s in pain sensation (Rush, A. M. and T. R.Cummins, Painful Research: Identification of a Small-Molecule Inhibitorthat Selectively Targets Na _(v)1.8 Sodium Channels. Mol Interv, 2007.7(4): p. 192-5); England, S., Voltage-gated sodium channels: the searchfor subtype-selective analgesics. Expert Opin Investig Drugs 17 (12), p.1849-64 (2008); Krafte, D. S. and Bannon, A. W., Sodium channels andnociception: recent concepts and therapeutic opportunities. Curr OpinPharmacol 8 (1), p. 50-56 (2008)). Na_(v)'s are the primary mediators ofthe rapid upstroke of the action potential of many excitable cell types(e.g. neurons, skeletal myocytes, cardiac myocytes), and thus arecritical for the initiation of signaling in those cells (Hille, Bertil,Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates,Inc., Sunderland, Mass., 2001)). Because of the role Na_(v)'s play inthe initiation and propagation of neuronal signals, antagonists thatreduce Na_(v) currents can prevent or reduce neural signaling and Na_(v)channels have long been considered likely targets to reduce pain inconditions where hyper-excitability is observed (Chahine, M., Chatelier,A., Babich, O., and Krupp, J. J., Voltage-gated sodium channels inneurological disorders. CNS Neurol Disord Drug Targets 7 (2), p. 144-58(2008)). Several clinically useful analgesics have been identified asinhibitors of Na_(v) channels. The local anesthetic drugs such aslidocaine block pain by inhibiting Na_(v) channels, and other compounds,such as carbamazepine, lamotrigine, and tricyclic antidepressants thathave proven effective at reducing pain have also been suggested to actby sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects oftheir mechanisms of action. Eur J Pain 6 Suppl A, p. 3-9 (2002); Wang,G. K., Mitchell, J., and Wang, S. Y., Block of persistent late Na⁺currents by antidepressant sertraline and paroxetine. J Membr Biol 222(2), p. 79-90 (2008)).

The Na_(v)'s form a subfamily of the voltage-gated ion channelsuper-family and comprises 9 isoforms, designated Nav1.1-Nav1.9. Thetissue localizations of the nine isoforms vary greatly. Nav1.4 is theprimary sodium channel of skeletal muscle, and Nav1.5 is primary sodiumchannel of cardiac myocytes. Na_(v)'s 1.7, 1.8 and 1.9 are primarilylocalized to the peripheral nervous system, while Na_(v)'s 1.1, 1.2,1.3, and 1.6 are neuronal channels found in both the central andperipheral nervous systems. The functional behaviors of the nineisoforms are similar but distinct in the specifics of theirvoltage-dependent and kinetic behavior (Catterall, W. A., Goldin, A. L.,and Waxman, S. G., International Union of Pharmacology. XLVII.Nomenclature and structure-function relationships of voltage-gatedsodium channels. Pharmacol Rev 57 (4), p. 397 (2005)).

Immediately upon their discovery, Na_(v)1.8 channels were identified aslikely targets for analgesia (Akopian, A. N., L. Sivilotti, and J. N.Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed bysensory neurons. Nature, 1996. 379(6562): p. 257-62). Since then,Na_(v)1.8 has been shown to be the most significant carrier of thesodium current that maintains action potential firing in small DRGneurons (Blair, N. T. and B. P. Bean, Roles of tetrodotoxin(TTX)-sensitive Na+ current, TTX-resistant Na⁺ current, and Ca²⁺ currentin the action potentials of nociceptive sensory neurons. J Neurosci.,2002. 22(23): p. 10277-90). Na_(v)1.8 is essential for spontaneousfiring in damaged neurons, like those that drive neuropathic pain (Roza,C., et al., The tetrodotoxin-resistant Na⁺ channel Na_(v)1.8 isessential for the expression of spontaneous activity in damaged sensoryaxons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6; Jarvis, M. F., etal., A-803467, a potent and selective Na_(v)1.8 sodium channel blocker,attenuates neuropathic and inflammatory pain in the rat. Proc Natl AcadSci. USA, 2007. 104(20): p. 8520-5; Joshi, S. K., et al., Involvement ofthe TTX-resistant sodium channel Nav1.8 in inflammatory and neuropathic,but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82;Lai, J., et al., Inhibition of neuropathic pain by decreased expressionof the tetrodotoxin-resistant sodium channel, Na_(v)1.8. Pain, 2002.95(1-2): p. 143-52; Dong, X. W., et al., Small interfering RNA-mediatedselective knockdown of Na(_(v))1.8 tetrodotoxin-resistant sodium channelreverses mechanical allodynia in neuropathic rats. Neuroscience, 2007.146(2): p. 812-21; Huang, H. L., et al., Proteomic profiling of neuromasreveals alterations in protein composition and local protein synthesisin hyper-excitable nerves. Mol Pain, 2008. 4: p. 33; Black, J. A., etal., Multiple sodium channel isoforms and mitogen-activated proteinkinases are present in painful human neuromas. Ann Neurol, 2008. 64(6):p. 644-53; Coward, K., et al., Immunolocalization of SNS/PN3 andNaN/SNS2 sodium channels in human pain states. Pain, 2000. 85(1-2): p.41-50; Yiangou, Y., et al., SNS/PN3 and SNS2/NaN sodium channel-likeimmunoreactivity in human adult and neonate injured sensory nerves. FEBSLett, 2000. 467(2-3): p. 249-52; Ruangsri, S., et al., Relationship ofaxonal voltage-gated sodium channel 1.8 (Na_(v)1.8) mRNA accumulation tosciatic nerve injury-induced painful neuropathy in rats. J Biol Chem.286(46): p. 39836-47). The small DRG neurons where Na_(v)1.8 isexpressed include the nociceptors critical for pain signaling. Na_(v)1.8is the primary channel that mediates large amplitude action potentialsin small neurons of the dorsal root ganglia (Blair, N. T. and B. P.Bean, Roles of tetrodotoxin (TTX)-sensitive Na⁺ current, TTX-resistantNa⁺ current, and Ca²⁺ current in the action potentials of nociceptivesensory neurons. J Neurosci., 2002. 22(23): p. 10277-90). Na_(v)1.8 isnecessary for rapid repetitive action potentials in nociceptors, and forspontaneous activity of damaged neurons. (Choi, J. S. and S. G. Waxman,Physiological interactions between Na_(v)1.7 and Na_(v)1.8 sodiumchannels: a computer simulation study. J Neurophysiol. 106(6): p.3173-84; Renganathan, M., T. R. Cummins, and S. G. Waxman, Contributionof Na(_(v))1.8 sodium channels to action potential electrogenesis in DRGneurons. J Neurophysiol., 2001. 86(2): p. 629-40; Roza, C., et al., Thetetrodotoxin-resistant Na⁺ channel Na_(v)1.8 is essential for theexpression of spontaneous activity in damaged sensory axons of mice. JPhysiol., 2003. 550(Pt 3): p. 921-6). In depolarized or damaged DRGneurons, Na_(v)1.8 appears to be the primary driver ofhyper-excitablility (Rush, A. M., et al., A single sodium channelmutation produces hyper- or hypoexcitability in different types ofneurons. Proc Natl Acad Sci USA, 2006. 103(21): p. 8245-50). In someanimal pain models, Na_(v)1.8 mRNA expression levels have been shown toincrease in the DRG (Sun, W., et al., Reduced conduction failure of themain axon of polymodal nociceptive C-fibres contributes to painfuldiabetic neuropathy in rats. Brain. 135(Pt 2): p. 359-75; Strickland, I.T., et al., Changes in the expression of NaV1.7, Na_(v)1.8 and Na_(v)1.9in a distinct population of dorsal root ganglia innervating the rat kneejoint in a model of chronic inflammatory joint pain. Eur J Pain, 2008.12(5): p. 564-72; Qiu, F., et al., Increased expression oftetrodotoxin-resistant sodium channels Na_(v)1.8 and Na_(v)1.9 withindorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett.512(2): p. 61-6).

The primary drawback to the known Na_(v) inhibitors is their poortherapeutic window, and this is likely a consequence of their lack ofisoform selectivity. Since Na_(v)1.8 is primarily restricted to theneurons that sense pain, selective Na_(v)1.8 blockers are unlikely toinduce the adverse events common to non-selective Na_(v) blockers.Accordingly, there remains a need to develop additional Na_(v) channelantagonists preferably those that are more Nav1.8 selective and morepotent with increased metabolic stability and with fewer side effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable salts and compositions thereof, are usefulas inhibitors of voltage-gated sodium channels.

These compounds have the general formula I:

or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable salts and compositionsare useful for treating or lessening the severity of a variety ofdiseases, disorders, or conditions, including, but not limited to,chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acutepain, inflammatory pain, cancer pain, idiopathic pain, multiplesclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiacarrhythmia.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R¹ is H, Cl, CH₃, CF₃ or cyclopropyl;R² is H, F, Cl, CN, CH₃, CF₃ or CHF₂;R³ is H, F, Cl, CN, CF₃, OCF₃ or CF₂CF₃;R⁴ is H;R⁵ is H, F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂;R^(5′) is H, F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂;R⁶ is H, F or Cl;R^(6′) is H, F or Cl; andR⁷ is H, F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂,provided that R¹, R², and R³ are not simultaneously hydrogen; andthat R⁵, R^(5′), R⁶, R^(6′), and R⁷ are not simultaneously hydrogen.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry,”Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry,”5^(th) Ed., Ed.: Smith, M. B. and March, J.,John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention can optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. As described herein, the variables informula I encompass specific groups, such as, for example, alkyl andcycloalkyl. As one of ordinary skill in the art will recognize,combinations of substituents envisioned by this invention are thosecombinations that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The phrase “optionally substituted” may be used interchangeably with thephrase “substituted or unsubstituted.” In general, the term“substituted,” whether preceded by the term “optionally” or not, refersto the replacement of hydrogen radicals in a given structure with theradical of a specified substituent. Specific substituents are describedabove in the definitions and below in the description of compounds andexamples thereof. Unless otherwise indicated, an optionally substitutedgroup can have a substituent at each substitutable position of thegroup, and when more than one position in any given structure can besubstituted with more than one substituent selected from a specifiedgroup, the substituent can be either the same or different at everyposition. A ring substituent, such as a heterocycloalkyl, can be boundto another ring, such as a cycloalkyl, to form a spiro-bicyclic ringsystem, e.g., both rings share one common atom. As one of ordinary skillin the art will recognize, combinations of substituents envisioned bythis invention are those combinations that result in the formation ofstable or chemically feasible compounds.

The phrase “up to,” as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 4” means any one of 0, 1, 2, 3, and 4.

The term “aliphatic,” “aliphatic group” or “alkyl” as used herein, meansa straight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms, and in yet other embodiments aliphatic groups contain 1-4aliphatic carbon atoms. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups.

The terms “cycloaliphatic” or “cycloalkyl” mean a monocyclic hydrocarbonring, or a polycyclic hydrocarbon ring system that is completelysaturated or that contains one or more units of unsaturation, but whichis not aromatic and has a single point of attachment to the rest of themolecule.

The term “polycyclic ring system,” as used herein, includes bicyclic andtricyclic 4- to 12-membered structures that form at least two rings,wherein the two rings have at least one atom in common (e.g., 2 atoms incommon) including fused, bridged, or spirocyclic ring systems.

The term “halogen” or “halo” as used herein, means F, Cl, Br or I.

Unless otherwise specified, the term “heterocycle,” “heterocyclyl,”“heterocycloaliphatic,” “heterocycloalkyl,” or “heterocyclic” as usedherein means non-aromatic, monocyclic, bicyclic, or tricyclic ringsystems in which one or more ring atoms in one or more ring members isan independently selected heteroatom. Heterocyclic ring can be saturatedor can contain one or more unsaturated bonds. In some embodiments, the“heterocycle,” “heterocyclyl,” “heterocycloaliphatic,”“heterocycloalkyl,” or “heterocyclic” group has three to fourteen ringmembers in which one or more ring members is a heteroatom independentlyselected from oxygen, sulfur, nitrogen, or phosphorus, and each ring inthe ring system contains 3 to 7 ring members.

The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus,or silicon; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation but is not aromatic.

The term “alkoxy,” or “thioalkyl,” as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring carbon atoms, wherein at least one ring in the system is aromaticand wherein each ring in the system contains 3 to 7 ring carbon atoms.The term “aryl” may be used interchangeably with the term “aryl ring.”

The term “heteroaryl,” used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy,” refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic.”

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Thus, included within the scope of the invention aretautomers of compounds of formula I. The structures also includezwitterionic forms of the compounds or salts of formula I whereappropriate.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched or isotopically-labeled atoms. Theisotopically-labeled compounds may have one or more atoms replaced by anatom having an atomic mass or mass number usually found in nature.Examples of isotopes present in compounds of formula I include isotopesof hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine andchlorine, such as, but not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O,³⁵S and ¹⁸F. Certain isotopically-labeled compounds of formula I, inaddition to being useful as therapeutic agents, are also useful in drugand/or substrate tissue distribution assays, as analytical tools or asprobes in other biological assays. In one aspect of the presentinvention, tritiated (e.g., ³H) and carbon-14 (e.g., ¹⁴C) isotopes areuseful given their ease of detectability. In another aspect of thepresent invention, replacement of one or more hydrogen atoms withheavier isotopes such as deuterium, (e.g., ²H) can afford certaintherapeutic advantages.

In one embodiment, the invention features a compound of formula I andthe attendant definitions, wherein R¹ is H. In another embodiment, R¹ isCl. In another embodiment, R¹ is CH₃. In another embodiment, R¹ is CF₃.In another embodiment, R¹ is cyclopropyl. In another embodiment, R¹ isH, CF₃ or Cl. In another embodiment, R¹ is H or CF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R² is H. In another embodiment,R² is F. In another embodiment, R² is Cl. In another embodiment, R² isCN. In another embodiment, R² is CH₃. In another embodiment, R² is CF₃.In another embodiment, R² is CHF₂. In another embodiment, R² is H, CF₃or Cl. In another embodiment, R² is H or CF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R³ is H. In another embodiment,R³ is F. In another embodiment, R³ is Cl. In another embodiment, R³ isCN. In another embodiment, R³ is CF₃. In another embodiment, R³ is OCF₃.In another embodiment, R³ is CF₂CF₃. In another embodiment, R³ is H,CF₃, Cl or OCF₃. In another embodiment, R³ is H, CF₃ or Cl.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R⁵ is H. In another embodiment,R⁵ is F. In another embodiment, R⁵ is Cl. In another embodiment, R⁵ isCH₃. In another embodiment, R⁵ is OCH₃. In another embodiment, R⁵ isOCH₂CH₃. In another embodiment, R⁵ is OCH₂CH₂CH₃. In another embodiment,R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R^(5′) is H. In anotherembodiment, R^(5′) is F. In another embodiment, R^(5′) is Cl. In anotherembodiment, R^(5′) is CH₃. In another embodiment, R^(5′) is OCH₃. Inanother embodiment, R^(5′) is OCH₂CH₃. In another embodiment, R^(5′) isOCH₂CH₂CH₃. In another embodiment, R^(5′) is OCHF₂.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R⁶ is H. In another embodiment,R⁶ is F. In another embodiment, R⁶ is Cl. In another embodiment, R⁶ is Hor F.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R^(6′) is H. In anotherembodiment, R^(6′) is F. In another embodiment, R^(6′) is Cl. In anotherembodiment, R^(6′) is H or F.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R⁷ is H. In another embodiment,R⁷ is F. In another embodiment, R⁷ is Cl. In another embodiment, R⁷ isOCH₃. In another embodiment, R⁷ is OCF₃. In another embodiment, R⁷ isOCH₂CH₃. In another embodiment, R⁷ is OCH(CH₃)₂. In another embodiment,R⁷ is OCHF₂. In another embodiment, R⁷ is F, Cl, OCH₃ or OCF₃. Inanother embodiment, R⁷ is F or OCH₃.

In another aspect, the invention provides a compound of formula I-A:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R² is F, Cl, CN, CH₃, CF₃ or CHF₂; andR⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In one embodiment, the invention features a compound of formula I-A andthe attendant definitions, wherein R² is F. In another embodiment, R² isCl. In another embodiment, R² is CN. In another embodiment, R² is CH₃.In another embodiment, R² is CF₃. In another embodiment, R² is CHF₂.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R⁷ is F. In another embodiment,R⁷ is Cl. In another embodiment, R⁷ is OCH₃. In another embodiment, R⁷is OCF₃, In another embodiment, R⁷ is OCH₂CH₃. In another embodiment, R⁷is OCH(CH₃)₂. In another embodiment, R⁷ is OCHF₂.

In another aspect, the invention provides a compound of formula I-B:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃; andR⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In one embodiment, the invention features a compound of formula I-B andthe attendant definitions, wherein R³ is F. In another embodiment, R³ isCl. In another embodiment, R³ is CN. In another embodiment, R³ is CF₃.In another embodiment, R³ is OCF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R⁷ is F. In another embodiment,R⁷ is Cl. In another embodiment, R⁷ is OCH₃. In another embodiment, R⁷is OCF₃. In another embodiment, R⁷ is OCH₂CH₃. In another embodiment, R⁷is OCH(CH₃)₂. In another embodiment, R⁷ is OCHF₂.

In another aspect, the invention provides a compound of formula I-C:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R¹ is Cl, CH₃, CF₃ or cyclopropyl;R⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; andR⁷ is F, Cl, OCH₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In one embodiment, the invention features a compound of formula I-C andthe attendant definitions, wherein R¹ is Cl. In another embodiment, R¹is CH₃. In another embodiment, R¹ is CF₃. In another embodiment, R¹ iscyclopropyl.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R⁵ is F. In another embodiment,R⁵ is Cl. In another embodiment, R⁵ is CH₃. In another embodiment, R⁵ isOCH₃. In another embodiment, R⁵ is OCH₂CH₃. In another embodiment, R⁵ isOCH₂CH₂CH₃. In another embodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R⁷ is F. In another embodiment,R⁷ is Cl. In another embodiment, R⁷ is OCH₃. In another embodiment, R⁷is OCH₂CH₃. In another embodiment, R⁷ is OCH(CH₃)₂. In anotherembodiment, R⁷ is OCHF₂.

In another aspect, the invention provides a compound of formula I-D:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R² is F, Cl, CN, CH₃, CF₃ or CHF₂;R⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; andR⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In one embodiment, the invention features a compound of formula I-D andthe attendant definitions, wherein R² is F. In another embodiment, R² isCl. In another embodiment, R² is CN. In another embodiment, R² is CH₃.In another embodiment, R² is CF₃. In another embodiment, R² is CHF₂. Inanother embodiment, R² is Cl or CF₃.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R⁵ is F. In another embodiment,R⁵ is Cl. In another embodiment, R⁵ is CH₃. In another embodiment, R⁵ isOCH₃. In another embodiment, R⁵ is OCH₂CH₃. In another embodiment, R⁵ isOCH₂CH₂CH₃. In another embodiment, R⁵ is OCHF₂. In another embodiment,R⁵ is F, Cl, CH₃ or OCH₃.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R⁷ is F. In another embodiment,R⁷ is Cl. In another embodiment, R⁷ is OCH₃. In another embodiment, R⁷is OCF₃. In another embodiment, R⁷ is OCH₂CH₃. In another embodiment, R⁷is OCH(CH₃)₂. In another embodiment, R⁷ is OCHF₂. In another embodiment,R⁷ is F, Cl, OCH₃ or OCF₃.

In another aspect, the invention provides a compound of formula I-E:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃;R⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; andR⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In one embodiment, the invention features a compound of formula I-E andthe attendant definitions, wherein R³ is F. In another embodiment, R³ isCl. In another embodiment, R³ is CN. In another embodiment, R³ is CF₃.In another embodiment, R³ is OCF₃. In another embodiment, R³ is CF₂CF₃.In another embodiment, R³ is Cl, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R⁵ is F. In another embodiment,R⁵ is Cl. In another embodiment, R⁵ is CH₃. In another embodiment, R⁵ isOCH₃. In another embodiment, R⁵ is OCH₂CH₃. In another embodiment, R⁵ isOCH₂CH₂CH₃. In another embodiment, R⁵ is OCHF₂. In another embodiment,R⁵ is F, Cl, CH₃ or OCH₃.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R⁷ is F. In another embodiment,R⁷ is Cl. In another embodiment, R⁷ is OCH₃. In another embodiment, R⁷is OCF₃. In another embodiment, R⁷ is OCH₂CH₃. In another embodiment, R⁷is OCH(CH₃)₂. In another embodiment, R⁷ is OCHF₂. In another embodiment,R⁷ is F, Cl, OCH₃ or OCF₃.

In another aspect, the invention provides a compound of formula I-F:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R¹ is Cl, CH₃, CF₃ or cyclopropyl;R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃; andR⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In one embodiment, the invention features a compound of formula I-F andthe attendant definitions, wherein R¹ is Cl. In another embodiment, R¹is CH₃. In another embodiment, R¹ is CF₃. In another embodiment, R¹ iscyclopropyl.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R³ is F. In another embodiment,R³ is Cl. In another embodiment, R³ is CN. In another embodiment, R³ isCF₃. In another embodiment, R³ is OCF₃. In another embodiment, R³ isCF₂CF₃.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R⁷ is F. In another embodiment,R⁷ is Cl. In another embodiment, R⁷ is OCH₃. In another embodiment, R⁷is OCF₃. In another embodiment, R⁷ is OCH₂CH₃. In another embodiment, R⁷is OCH(CH₃)₂. In another embodiment, R⁷ is OCHF₂.

In another aspect, the invention provides a compound of formula I-G:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R² is F, Cl, CN, CH₃, CF₃ or CHF₂;R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃; andR⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In one embodiment, the invention features a compound of formula I-G andthe attendant definitions, wherein R² is F. In another embodiment, R² isCl. In another embodiment, R² is CN. In another embodiment, R² is CH₃.In another embodiment, R² is CF₃. In another embodiment, R² is CHF₂.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein R³ is F. In another embodiment,R³ is Cl. In another embodiment, R³ is CN. In another embodiment, R³ isCF₃. In another embodiment, R³ is OCF₃. In another embodiment, R³ isCF₂CF₃.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein R⁷ is F. In another embodiment,R⁷ is Cl. In another embodiment, R⁷ is OCH₃. In another embodiment, R⁷is OCF₃. In another embodiment, R⁷ is OCH₂CH₃. In another embodiment, R⁷is OCH(CH₃)₂. In another embodiment, R⁷ is OCHF₂.

In another aspect, the invention provides a compound of formula I-H:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R¹ is Cl, CH₃, CF₃ or cyclopropyl;R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃;R⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; andR⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In one embodiment, the invention features a compound of formula I-H andthe attendant definitions, wherein R¹ is Cl. In another embodiment, R¹is CH₃. In another embodiment, R¹ is CF₃. In another embodiment, R¹ iscyclopropyl.

In another embodiment, the invention features a compound of formula I-Hand the attendant definitions, wherein R³ is F. In another embodiment,R³ is Cl. In another embodiment, R³ is CN. In another embodiment, R³ isCF₃. In another embodiment, R³ is OCF₃. In another embodiment, R³ isCF₂CF₃.

In another embodiment, the invention features a compound of formula I-Hand the attendant definitions, wherein R⁵ is F. In another embodiment,R⁵ is Cl. In another embodiment, R⁵ is CH₃. In another embodiment, R⁵ isOCH₃. In another embodiment, R⁵ is OCH₂CH₃. In another embodiment, R⁵ isOCH₂CH₂CH₃. In another embodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Hand the attendant definitions, wherein R⁷ is F. In another embodiment,R⁷ is F. In another embodiment, R⁷ is Cl. In another embodiment, R⁷ isOCH₃. In another embodiment, R⁷ is OCF₃. In another embodiment, R⁷ isOCH₂CH₃. In another embodiment, R⁷ is OCH(CH₃)₂. In another embodiment,R⁷ is OCHF₂.

In another aspect, the invention provides a compound of formula I-J:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R² is F, Cl, CN, CH₃, CF₃ or CHF₂;R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃;R⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; andR⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In one embodiment, the invention features a compound of formula I-J andthe attendant definitions, wherein R² is F. In another embodiment, R² isCl. In another embodiment, R² is CN. In another embodiment, R² is CH₃.In another embodiment, R² is CF₃. In another embodiment, R² is CHF₂.

In another embodiment, the invention features a compound of formula I-Jand the attendant definitions, wherein R³ is F. In another embodiment,R³ is Cl. In another embodiment, R³ is CN. In another embodiment, R³ isCF₃. In another embodiment, R³ is OCF₃. In another embodiment, R³ isCF₂CF₃.

In another embodiment, the invention features a compound of formula I-Jand the attendant definitions, wherein R⁵ is F. In another embodiment,R⁵ is Cl. In another embodiment, R⁵ is CH₃. In another embodiment, R⁵ isOCH₃. In another embodiment, R⁵ is OCH₂CH₃. In another embodiment, R⁵ isOCH₂CH₂CH₃. In another embodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Jand the attendant definitions, wherein R⁷ is F. In another embodiment,R⁷ is Cl. In another embodiment, R⁷ is OCH₃. In another embodiment, R⁷is OCF₃. In another embodiment, R⁷ is OCH₂CH₃. In another embodiment, R⁷is OCH(CH₃)₂. In another embodiment, R⁷ is OCHF₂.

In another aspect, the invention provides a compound of formula I-K

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R¹ is Cl, CH₃, CF₃ or cyclopropyl; andR⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂;

In another embodiment, the invention features a compound of formula I-Kand the attendant definitions, wherein R¹ is Cl. In another embodiment,R¹ is CH₃. In another embodiment, R¹ is CF₃. In another embodiment, R¹is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Kand the attendant definitions, wherein R⁵ is F. In another embodiment,R⁵ is Cl. In another embodiment, R⁵ is CH₃. In another embodiment, R⁵ isOCH₃. In another embodiment, R⁵ is OCH₂CH₃. In another embodiment, R⁵ isOCH₂CH₂CH₃. In another embodiment, R⁵ is OCHF₂.

In another aspect, the invention provides a compound of formula I-L

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃;R⁶ is F or Cl; andR⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In another embodiment, the invention features a compound of formula I-Land the attendant definitions, wherein R³ is F. In another embodiment,R³ is Cl. In another embodiment, R³ is CN. In another embodiment, R³ isCF₃. In another embodiment, R³ is OCF₃. In another embodiment, R³ isCF₂CF₃.

In another embodiment, the invention features a compound of formula I-Land the attendant definitions, wherein R⁶ is F. In another embodiment,R⁶ is Cl.

In another embodiment, the invention features a compound of formula I-Land the attendant definitions, wherein R⁷ is F. In another embodiment,R⁷ is Cl. In another embodiment, R⁷ is OCH₃. In another embodiment, R⁷is OCF₃. In another embodiment, R⁷ is OCH₂CH₃. In another embodiment, R⁷is OCH(CH₃)₂. In another embodiment, R⁷ is OCHF₂.

In another aspect, the invention provides a compound of formula I-M

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃; andR⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂.

In another embodiment, the invention features a compound of formula I-Mand the attendant definitions, wherein R³ is F. In another embodiment,R³ is Cl. In another embodiment, R³ is CN. In another embodiment, R³ isCF₃. In another embodiment, R³ is OCF₃. In another embodiment, R³ isCF₂CF₃.

In another embodiment, the invention features a compound of formula I-Mand the attendant definitions, wherein R⁵ is F. In another embodiment,R⁵ is Cl. In another embodiment, R⁵ is CH₃. In another embodiment, R⁵ isOCH₃. In another embodiment, R⁵ is OCH₂CH₃. In another embodiment, R⁵ isOCH₂CH₂CH₃. In another embodiment, R⁵ is OCHF₂.

In another aspect, the invention provides a compound of formula I-N

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃;R⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; andR⁶ is F or Cl.

In another embodiment, the invention features a compound of formula I-Nand the attendant definitions, wherein R³ is F. In another embodiment,R³ is Cl. In another embodiment, R³ is CN. In another embodiment, R³ isCF₃. In another embodiment, R³ is OCF₃. In another embodiment, R³ isCF₂CF₃.

In another embodiment, the invention features a compound of formula I-Nand the attendant definitions, wherein R⁵ is F. In another embodiment,R⁵ is Cl. In another embodiment, R⁵ is CH₃. In another embodiment, R⁵ isOCH₃. In another embodiment, R⁵ is OCH₂CH₃. In another embodiment, R⁵ isOCH₂CH₂CH₃. In another embodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Nand the attendant definitions, wherein R⁶ is F. In another embodiment,R⁶ is Cl.

In another aspect, the invention provides a compound of formula I-O

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:R¹ is Cl, CH₃, CF₃ or cyclopropyl;R³ is F, Cl, CN, CF₃, OCF₃ or CF₂CF₃;R⁶ is F, or Cl; andR⁷ is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.

In another embodiment, the invention features a compound of formula I-Oand the attendant definitions, wherein R¹ is Cl. In another embodiment,R¹ is CH₃. In another embodiment, R¹ is CF₃. In another embodiment, R¹is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Oand the attendant definitions, wherein R³ is F. In another embodiment,R³ is Cl. In another embodiment, R³ is CN. In another embodiment, R³ isCF₃. In another embodiment, R³ is OCF₃. In another embodiment, R³ isCF₂CF₃.

In another embodiment, the invention features a compound of formula I-Oand the attendant definitions, wherein R⁶ is F. In another embodiment,R⁶ is Cl.

In another embodiment, the invention features a compound of formula I-Oand the attendant definitions, wherein R⁷ is F. In another embodiment,R⁷ is Cl. In another embodiment, R⁷ is OCH₃. In another embodiment, R⁷is OCF₃. In another embodiment, R⁷ is OCH₂CH₃. In another embodiment, R⁷is OCH(CH₃)₂. In another embodiment, R⁷ is OCHF₂.

In another embodiment, the invention features a compound of formula I,wherein the compound or a pharmaceutically acceptable salt thereof, isselected from Table 1. Compounds names in Table 1 were generated usingChemBioDrawUltra version 12.0 from Cambridge Soft/Chem Office 2010.

TABLE 1 Compound Numbers, Structures and Chemical Names 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

In one embodiment, the compound is2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide ora pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide ora pharmaceutically acceptable salt thereof.

In another embodiment, the compound is4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide ora pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide or apharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamideor a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide ora pharmaceutically acceptable salt thereof.

In another embodiment, the compound is2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide or apharmaceutically acceptable salt thereof.

In another embodiment, the compound isN-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide.

Salts, Compositions, Uses, Formulation, Administration and AdditionalAgents

Pharmaceutically Acceptable Salts and Compositions

As discussed herein, the invention provides compounds that areinhibitors of voltage-gated sodium channels, and thus the presentcompounds are useful for the treatment of diseases, disorders, andconditions including, but not limited to chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence or cardiac arrhythmia. Accordingly, in anotheraspect of the invention, pharmaceutically acceptable compositions areprovided, wherein these compositions comprise any of the compounds asdescribed herein, and optionally comprise a pharmaceutically acceptablecarrier, adjuvant or vehicle. In certain embodiments, these compositionsoptionally further comprise one or more additional therapeutic agents.In another embodiment, the invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound of formula I or a pharmaceutically acceptable salt thereof ofand one or more pharmaceutically acceptable carriers or vehicles.

It will also be appreciated that certain of the compounds of inventioncan exist in free form for treatment, or where appropriate, as apharmaceutically acceptable derivative thereof. According to theinvention, a pharmaceutically acceptable derivative includes, but is notlimited to, pharmaceutically acceptable salts, esters, salts of suchesters, or any other adduct or derivative which upon administration to asubject in need is capable of providing, directly or indirectly, acompound as otherwise described herein, or a metabolite or residuethereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described herein, the pharmaceutically acceptable compositions of theinvention additionally comprise a pharmaceutically acceptable carrier,adjuvant, or vehicle, which, as used herein, includes any and allsolvents, diluents, or other liquid vehicle, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. Remington's PharmaceuticalSciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton,Pa., 1980) discloses various carriers used in formulatingpharmaceutically acceptable compositions and known techniques for thepreparation thereof. Except insofar as any conventional carrier mediumis incompatible with the compounds of the invention, such as byproducing any undesirable biological effect or otherwise interacting ina deleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, serum proteins,such as human serum albumin, buffer substances such as phosphates,glycine, sorbic acid, or potassium sorbate, partial glyceride mixturesof saturated vegetable fatty acids, water, salts or electrolytes, suchas protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In another aspect, the invention features a pharmaceutical compositioncomprising the compound of the invention and a pharmaceuticallyacceptable carrier.

In another aspect, the invention features a pharmaceutical compositioncomprising a therapeutically effective amount of the compound or apharmaceutically acceptable salt thereof of the compounds of formula Iand one or more pharmaceutically acceptable carriers or vehicles.

Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a subject comprising administering tothe subject a compound of formula I or a pharmaceutically acceptablesalt thereof or a pharmaceutical composition thereof. In another aspect,the voltage-gated sodium channel is Nav1.8.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence or cardiac arrhythmia comprising administering aneffective amount of a compound, a pharmaceutically acceptable saltthereof or a pharmaceutical composition of the compounds of formula I.

In another aspect, the invention features a method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence or cardiac arrhythmia comprising administering aneffective amount of a compound or a pharmaceutically acceptable saltthereof or a pharmaceutical composition of the compounds of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of gut pain wherein gut paincomprises inflammatory bowel disease pain, Crohn's disease pain orinterstitial cystitis pain.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain whereinneuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia,painful HIV-associated sensory neuropathy, trigeminal neuralgia, burningmouth syndrome, post-amputation pain, phantom pain, painful neuroma;traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinalstenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerveavulsion injury, brachial plexus avulsion injury; complex regional painsyndrome, drug therapy induced neuralgia, cancer chemotherapy inducedneuralgia, anti-retroviral therapy induced neuralgia; post spinal cordinjury pain, idiopathic small-fiber neuropathy, idiopathic sensoryneuropathy or trigeminal autonomic cephalalgia.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of musculoskeletal pain whereinmusculoskeletal pain comprises osteoarthritis pain, back pain, coldpain, burn pain or dental pain.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of idiopathic pain whereinidiopathic pain comprises fibromyalgia pain.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of inflammatory pain whereininflammatory pain comprises rheumatoid arthritis pain or vulvodynia.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence or cardiac arrhythmia comprising administering aneffective amount of a compound or a pharmaceutically acceptable saltthereof or a pharmaceutical composition of the compounds of formula Iwith one or more additional therapeutic agents administered concurrentlywith, prior to, or subsequent to treatment with the compound orpharmaceutical composition.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of gut pain, wherein gut paincomprises inflammatory bowel disease pain, Crohn's disease pain orinterstitial cystitis pain wherein said method comprises administeringan effective amount of a compound, a pharmaceutically acceptable saltthereof or a pharmaceutical composition of the compounds of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain, whereinneuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia,painful HIV-associated sensory neuropathy, trigeminal neuralgia, burningmouth syndrome, post-amputation pain, phantom pain, painful neuroma,traumatic neuroma, Morton's neuroma; nerve entrapment injury, spinalstenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerveavulsion injury, brachial plexus avulsion injury; complex regional painsyndrome, drug therapy induced neuralgia, cancer chemotherapy inducedneuralgia, anti-retroviral therapy induced neuralgia; post spinal cordinjury pain, idiopathic small-fiber neuropathy, idiopathic sensoryneuropathy or trigeminal autonomic cephalalgia wherein said methodcomprises administering an effective amount of a compound, apharmaceutically acceptable salt thereof or a pharmaceutical compositionof the compounds of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of musculoskeletal pain, whereinmusculoskeletal pain comprises osteoarthritis pain, back pain, coldpain, burn pain or dental pain wherein said method comprisesadministering an effective amount of a compound, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition of the compoundsof formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of inflammatory pain, whereininflammatory pain comprises rheumatoid arthritis pain or vulvodyniawherein said method comprises administering an effective amount of acompound, a pharmaceutically acceptable salt thereof or a pharmaceuticalcomposition of the compounds of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of idiopathic pain, whereinidiopathic pain comprises fibromyalgia pain wherein said methodcomprises administering an effective amount of a compound, apharmaceutically acceptable salt thereof or a pharmaceutical compositionof the compounds of formula I.

In yet another aspect, the invention features a method wherein thesubject is treated with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith an effective amount of a compound, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition of the compounds of formulaI.

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a subject comprising administering tothe subject an effective amount of a compound, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition of the compoundsof formula I. In another aspect, the voltage-gated sodium channel isNav1.8.

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a biological sample comprisingcontacting the biological sample with an effective amount of a compound,a pharmaceutically acceptable salt thereof or a pharmaceuticalcomposition of the compounds of formula I. In another aspect, thevoltage-gated sodium channel is Nav1.8.

In another aspect, the invention features a method of treating orlessening the severity in a subject of acute pain, chronic pain,neuropathic pain, inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatricdisorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia,movement disorders, neuroendocrine disorders, ataxia, multiplesclerosis, irritable bowel syndrome, incontinence, visceral pain,osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head pain, neck pain, severe pain,intractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, cancer pain, stroke, cerebral ischemia, traumatic brain injury,amyotrophic lateral sclerosis, stress induced angina, exercise inducedangina, palpitations, hypertension, or abnormal gastro-intestinalmotility, comprising administering an effective amount of a compound, apharmaceutically acceptable salt thereof or a pharmaceutical compositionof the compounds of formula I.

In another aspect, the invention features a method of treating orlessening the severity in a subject of femur cancer pain; non-malignantchronic bone pain; rheumatoid arthritis; osteoarthritis; spinalstenosis; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,abdominal pain; pancreatic pain; IBS pain; chronic and acute headachepain; migraine; tension headache, cluster headaches; chronic and acuteneuropathic pain, post-herpetic neuralgia; diabetic neuropathy;HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Toothneuropathy; hereditary sensory neuropathies; peripheral nerve injury;painful neuromas; ectopic proximal and distal discharges; radiculopathy;chemotherapy induced neuropathic pain; radiotherapy-induced neuropathicpain; post-mastectomy pain; central pain; spinal cord injury pain;post-stroke pain; thalamic pain; complex regional pain syndrome; phantompain; intractable pain; acute pain, acute post-operative pain; acutemusculoskeletal pain; joint pain; mechanical low back pain; neck pain;tendonitis; injury pain; exercise pain; acute visceral pain;pyelonephritis; appendicitis; cholecystitis; intestinal obstruction;hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acuteobstetric pain, labor pain; cesarean section pain; acute inflammatory,burn and trauma pain; acute intermittent pain, endometriosis; acuteherpes zoster pain; sickle cell anemia; acute pancreatitis; breakthroughpain; orofacial pain including sinusitis pain, dental pain; multiplesclerosis (MS) pain; pain in depression; leprosy pain; Behcet's diseasepain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painfullegs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry'sdisease pain; bladder and urogenital disease, including, urinaryincontinence; hyperactivity bladder; painful bladder syndrome;interstitial cystitis (IC); prostatitis; complex regional pain syndrome(CRPS), type I and type II; widespread pain, paroxysmal extreme pain,pruritis, tinnitus, or angina-induced pain, comprising administering aneffective amount of a compound, a pharmaceutically acceptable saltthereof or a pharmaceutical composition of the compounds of formula I.

In another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain comprisingadministering an effective amount of a compound, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition of the compoundsof formula I. In one aspect, the neuropathic pain is selected frompost-herpetic neuralgia, diabetic neuralgia, painful HIV-associatedsensory neuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma, traumatic neuroma,Morton's neuroma, nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury,brachial plexus avulsion, complex regional pain syndrome, drug therapyinduced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia, post spinal cord injury pain,idiopathic small-fiber neuropathy, idiopathic sensory neuropathy ortrigeminal autonomic cephalalgia.

Manufacture of Medicaments

In one aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in inhibiting a voltage-gated sodium channel. Inanother aspect, the voltage-gated sodium channel is Nav1.8.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity in a subject ofchronic pain, gut pain, neuropathic pain, musculoskeletal pain, acutepain, inflammatory pain, cancer pain, idiopathic pain, multiplesclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiacarrhythmia.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity in a subject ofgut pain, wherein gut pain comprises inflammatory bowel disease pain,Crohn's disease pain or interstitial cystitis pain.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in a treating or lessening the severity in a subjectof neuropathic pain, wherein neuropathic pain comprises post-herpeticneuralgia, diabetic neuralgia, painful HIV-associated sensoryneuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma, traumatic neuroma,Morton's neuroma; nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury,brachial plexus avulsion injury; complex regional pain syndrome, drugtherapy induced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia; post spinal cord injury pain,idiopathic small-fiber neuropathy, idiopathic sensory neuropathy ortrigeminal autonomic cephalalgia.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity in a subject ofmusculoskeletal pain, wherein musculoskeletal pain comprisesosteoarthritis pain, back pain, cold pain, burn pain or dental pain.

In yet another aspect, the invention the invention provides the use of acompound or pharmaceutical composition described herein for themanufacture of a medicament for use in treating or lessening theseverity in a subject of inflammatory pain, wherein inflammatory paincomprises rheumatoid arthritis pain or vulvodynia.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity in a subject ofidiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament in combination with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith the compound or pharmaceutical composition.

In another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity of acute pain,chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine,cluster headaches, trigeminal neuralgia, herpetic neuralgia, generalneuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders,psychiatric disorders, anxiety, depression, dipolar disorder, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head pain, neck pain, severe pain,intractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, cancer pain, stroke, cerebral ischemia, traumatic brain injury,amyotrophic lateral sclerosis, stress induced angina, exercise inducedangina, palpitations, hypertension, or abnormal gastro-intestinalmotility.

In another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity of femur cancerpain; non-malignant chronic bone pain; rheumatoid arthritis;osteoarthritis; spinal stenosis; neuropathic low back pain; myofascialpain syndrome; fibromyalgia; temporomandibular joint pain; chronicvisceral pain, abdominal pain; pancreatic pain; IBS pain; chronic andacute headache pain; migraine; tension headache, including, clusterheadaches; chronic and acute neuropathic pain, post-herpetic neuralgia;diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia;Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies;peripheral nerve injury; painful neuromas; ectopic proximal and distaldischarges; radiculopathy; chemotherapy induced neuropathic pain;radiotherapy-induced neuropathic pain; post-mastectomy pain; centralpain; spinal cord injury pain; post-stroke pain; thalamic pain; complexregional pain syndrome; phantom pain; intractable pain; acute pain,acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury/exercise pain;acute visceral pain; pyelonephritis; appendicitis; cholecystitis;intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain,renal colic pain, acute obstetric pain, labor pain; cesarean sectionpain; acute inflammatory, burn and trauma pain; acute intermittent pain,endometriosis; acute herpes zoster pain; sickle cell anemia; acutepancreatitis; breakthrough pain; orofacial pain including sinusitispain, dental pain; multiple sclerosis (MS) pain; pain in depression;leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain; Fabry's disease pain; bladder and urogenitaldisease, including, urinary incontinence; hyperactivity bladder; painfulbladder syndrome; interstitial cystitis (IC); prostatitis; complexregional pain syndrome (CRPS), type I and type II; widespread pain,paroxysmal extreme pain, pruritis, tinnitus, or angina-induced pain.

In another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity of neuropathicpain. In one aspect, the neuropathic pain is selected from post-herpeticneuralgia, diabetic neuralgia, painful HIV-associated sensoryneuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma, traumatic neuroma,Morton's neuroma, nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury,brachial plexus avulsion, complex regional pain syndrome, drug therapyinduced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia, post spinal cord injury pain,idiopathic small-fiber neuropathy, idiopathic sensory neuropathy ortrigeminal autonomic cephalalgia.

Administration of Pharmaceutically Acceptable Salts and Compositions

In certain embodiments of the invention an “effective amount” of thecompound, a pharmaceutically acceptable salt thereof or pharmaceuticallyacceptable composition is that amount effective for treating orlessening the severity of one or more of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence or cardiac arrhythmia.

The compounds and compositions, according to the method of theinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of the pain or non-pain diseases recited herein. The exactamount required will vary from subject to subject, depending on thespecies, age, and general condition of the subject, the severity of theinfection, the particular agent, its mode of administration, and thelike. The compounds of the invention are preferably formulated in dosageunit form for ease of administration and uniformity of dosage. Theexpression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the subject to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular subject or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the subject; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts. The term “subject” or “patient,” as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the invention, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms are prepared by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium channels. In one embodiment, thecompounds and compositions of the invention are inhibitors of Na_(v)1.8and thus, without wishing to be bound by any particular theory, thecompounds and compositions are particularly useful for treating orlessening the severity of a disease, condition, or disorder whereactivation or hyperactivity of Na_(v)1.8 is implicated in the disease,condition, or disorder. When activation or hyperactivity of Na_(v)1.8 isimplicated in a particular disease, condition, or disorder, the disease,condition, or disorder may also be referred to as a “Na_(v)1.8-mediateddisease, condition or disorder.” Accordingly, in another aspect, theinvention provides a method for treating or lessening the severity of adisease, condition, or disorder where activation or hyperactivity ofNa_(v)1.8 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNa_(v)1.8 may be assayed according to methods described generally in theExamples herein, or according to methods available to one of ordinaryskill in the art.

Additional Therapeutic Agents

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the invention can be employed in combinationtherapies, that is, the compounds and pharmaceutically acceptablecompositions can be administered concurrently with, prior to, orsubsequent to, one or more other desired therapeutics or medicalprocedures. In one embodiment, the subject is treated with one or moreadditional therapeutic agents administered concurrently with, prior to,or subsequent to treatment with the compound or pharmaceuticalcomposition of formula I of the present invention. The particularcombination of therapies (therapeutics or procedures) to employ in acombination regimen will take into account compatibility of the desiredtherapeutics and/or procedures and the desired therapeutic effect to beachieved. It will also be appreciated that the therapies employed mayachieve a desired effect for the same disorder (for example, aninventive compound may be administered concurrently with another agentused to treat the same disorder), or they may achieve different effects(e.g., control of any adverse effects). As used herein, additionaltherapeutic agents that are normally administered to treat or prevent aparticular disease, or condition, are known as “appropriate for thedisease, or condition, being treated.” For example, exemplary additionaltherapeutic agents include, but are not limited to: nonopioid analgesics(indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin;naphthylalkanones such sa Nabumetone; oxicams such as Piroxicam;para-aminophenol derivatives, such as Acetaminophen; propionic acidssuch as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen,Naproxen sodium, Oxaprozin; salicylates such as Aspirin, Cholinemagnesium trisalicylate, Diflunisal; fenamates such as meclofenamicacid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid(narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone,Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone,Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, andPentazocine). Additionally, nondrug analgesic approaches may be utilizedin conjunction with administration of one or more compounds of theinvention. For example, anesthesiologic (intraspinal infusion, neuralblockade), neurosurgical (neurolysis of CNS pathways), neurostimulatory(transcutaneous electrical nerve stimulation, dorsal columnstimulation), physiatric (physical therapy, orthotic devices,diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, orbehavioral methods) approaches may also be utilized. Additionalappropriate therapeutic agents or approaches are described generally inThe Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L.Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.,2011, and the Food and Drug Administration website, www.fda.gov, theentire contents of which are hereby incorporated by reference.

In another embodiment, the additional therapeutic agent is an Na_(v) 1.7inhibitor. Na_(v) 1.7 and Na_(v) 1.8 ion channels are both highlyexpressed in the sensory neurons of the dorsal root ganglion, where painsignals originate, but the distinct functional behavior of the twochannels leads them to fulfill distinct and complementary roles inneuronal excitability. Na_(v)1.7 controls the general sensitivity ofnociceptive neurons, and initiating the painful signal in a nociceptor.Na_(v)1.8 amplifies and sustains the pain signal once it has beeninitiated. Because of these distinct roles, inhibiting both channelsshould increase the effectiveness of pain relief Preclinical geneticknockout mice support this idea, as double knockouts of Na_(v)1.7 andNa_(v)1.8 channels in the sensory DRG neurons surprisingly diminishnociceptive behaviors to a greater degree than knockout of eitherchannel alone.

In another embodiment, additional appropriate therapeutic agents areselected from the following:

-   -   (1) an opioid analgesic, e.g. morphine, heroin, hydromorphone,        oxymorphone, levorphanol, levallorphan, methadone, meperidine,        fentanyl, cocaine, codeine, dihydrocodeine, oxycodone,        hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone,        naltrexone, buprenorphine, butorphanol, nalbuphine or        pentazocine;    -   (2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,        diclofenac, diflunisal, etodolac, fenbufen, fenoprofen,        flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen,        ketorolac, meclofenamic acid, mefenamic acid, meloxicam,        nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,        oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac,        tolmetin or zomepirac;    -   (3) a barbiturate sedative, e.g. amobarbital, aprobarbital,        butabarbital, butalbital, mephobarbital, metharbital,        methohexital, pentobarbital, phenobarbital, secobarbital,        talbutal, thiamylal or thiopental;    -   (4) a benzodiazepine having a sedative action, e.g.        chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam,        oxazepam, temazepam or triazolam;    -   (5) a histamine (H₁) antagonist having a sedative action, e.g.        diphenhydramine, pyrilamine, promethazine, chlorpheniramine or        chlorcyclizine;    -   (6) a sedative such as glutethimide, meprobamate, methaqualone        or dichloralphenazone;    -   (7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol,        chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;    -   (8) an NMDA receptor antagonist, e.g.        dextromethorphan((+)-3-hydroxy-N-methylmorphinan) or its        metabolite dextrorphan((+)-3-hydroxy-N-methylmorphinan),        ketamine, memantine, pyrroloquinoline quinine,        cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,        EN-3231 (MorphiDex®), a combination formulation of morphine and        dextromethorphan), topiramate, neramexane or perzinfotel        including an NR2B antagonist, e.g. ifenprodil, traxoprodil or        (−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;    -   (9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,        guanfacine, dexmedetomidine, modafinil, or        4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)        quinazoline;    -   (10) a tricyclic antidepressant, e.g. desipramine, imipramine,        amitriptyline or nortriptyline;    -   (11) an anticonvulsant, e.g. carbamazepine (Tegretol®),        lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;    -   (12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or        NK-1 antagonist, e.g.        (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione        (TAK-637),        5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one        (MK-869), aprepitant, lanepitant, dapitant or        3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine        (2S,3S);    -   (13) a muscarinic antagonist, e.g. oxybutynin, tolterodine,        propiverine, tropsium chloride, darifenacin, solifenacin,        temiverine and ipratropium;    -   (14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib,        parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;    -   (15) a coal-tar analgesic, in particular paracetamol;    -   (16) a neuroleptic such as droperidol, chlorpromazine,        haloperidol, perphenazine, thioridazine, mesoridazine,        trifluoperazine, fluphenazine, clozapine, olanzapine,        risperidone, ziprasidone, quetiapine, sertindole, aripiprazole,        sonepiprazole, blonanserin, iloperidone, perospirone,        raclopride, zotepine, bifeprunox, asenapine, lurasidone,        amisulpride, balaperidone, palindore, eplivanserin, osanetant,        rimonabant, meclinertant, Miraxion® or sarizotan;    -   (17) a vanilloid receptor agonist (e.g. resinferatoxin or        civamide) or antagonist (e.g. capsazepine, GRC-15300);    -   (18) a beta-adrenergic such as propranolol;    -   (19) a local anaesthetic such as mexiletine;    -   (20) a corticosteroid such as dexamethasone;    -   (21) a 5-HT receptor agonist or antagonist, particularly a        5-HT_(1B/1D) agonist such as eletriptan, sumatriptan,        naratriptan, zolmitriptan or rizatriptan;    -   (22) a 5-HT_(2A) receptor antagonist such as        R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol        (MDL-100907);    -   (23) a cholinergic (nicotinic) analgesic, such as ispronicline        (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine        (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine        (ABT-594) or nicotine;    -   (24) Tramadol, Tramadol ER (Ultram ER®), Tapentadol ER        (Nucynta®);    -   (25) a PDE5 inhibitor, such as        5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one        (sildenafil),        (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]-pyrido[3,4-b]indole-1,4-dione        (IC-351 or tadalafil),        2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one        (vardenafil),        5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,        5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-c]pyrimidin-7-one,        5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,        4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,        3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;    -   (26) an alpha-2-delta ligand such as gabapentin (Neurontin®),        gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®),        pregabalin (Lyrica®), 3-methyl gabapentin,        (1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic        acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,        (3S,5R)-3-amino-5-methyl-heptanoic acid,        (3S,5R)-3-amino-5-methyl-octanoic acid,        (2S,4S)-4-(3-chlorophenoxy)proline,        (2S,4S)-4-(3-fluorobenzyl)-proline,        [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,        3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,        C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,        (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,        (3S,5R)-3-aminomethyl-5-methyl-octanoic acid,        (3S,5R)-3-amino-5-methyl-nonanoic acid,        (3S,5R)-3-amino-5-methyl-octanoic acid,        (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and        (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;    -   (27) a cannabinoid such as KHK-6188;    -   (28) metabotropic glutamate subtype 1 receptor (mGluR1)        antagonist;    -   (29) a serotonin reuptake inhibitor such as sertraline,        sertraline metabolite demethylsertraline, fluoxetine,        norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine,        paroxetine, citalopram, citalopram metabolite        desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine,        ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone,        cericlamine and trazodone;    -   (30) a noradrenaline (norepinephrine) reuptake inhibitor, such        as maprotiline, lofepramine, mirtazepine, oxaprotiline,        fezolamine, tomoxetine, mianserin, bupropion, bupropion        metabolite hydroxybupoprion, nomifensine and viloxazine        (Vivalan®), especially a selective noradrenaline reuptake        inhibitor such as reboxetine, in particular (S,S)-reboxetine;    -   (31) a dual serotonin-noradrenaline reuptake inhibitor, such as        venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,        clomipramine, clomipramine metabolite desmethylclomipramine,        duloxetine (Cymbalta®), milnacipran and imipramine;    -   (32) an inducible nitric oxide synthase (iNOS) inhibitor such as        S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,        S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,        5-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,        (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic        acid,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile;        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,        (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,        N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine,        NXN-462, or guanidinoethyldisulfide;    -   (33) an acetylcholinesterase inhibitor such as donepezil;    -   (34) a prostaglandin E2 subtype 4 (EP4) antagonist such as        N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide        or        4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic        acid;    -   (35) a leukotriene B4 antagonist; such as        1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic        acid (CP-105696),        5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric        acid (ONO-4057) or DPC-11870;    -   (36) a 5-lipoxygenase inhibitor, such as zileuton,        6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone        (ZD-2138), or        2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504);    -   (37) a sodium channel blocker, such as lidocaine, lidocaine plus        tetracaine cream (ZRS-201) or eslicarbazepine acetate;    -   (38) an Na_(v)1.7 blocker, such as XEN-402 and such as those        disclosed in WO2011/140425; WO2012/106499; WO2012/112743;        WO2012/125613; WO2013067248 or PCT/US2013/21535 the entire        contents of each application hereby incorporated by reference.    -   (39) an Na_(v)1.8 blocker, such as those disclosed in        WO2008/135826 and WO2006/011050 the entire contents of each        application hereby incorporated by reference.    -   (40) a combined Na_(v)1.7 and Na_(v)1.8 blocker, such as        DSP-2230 or BL-1021;    -   (41) a 5-HT3 antagonist, such as ondansetron;    -   (42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®,        Qutenza®); and the pharmaceutically acceptable salts and        solvates thereof;    -   (43) a nicotinic receptor antagonist, such as varenicline;    -   (44) an N-type calcium channel antagonist, such as Z-160;    -   (45) a nerve growth factor antagonist, such as tanezumab;    -   (46) an endopeptidase stimulant, such as senrebotase;    -   (47) an angiotensin II antagonist, such as EMA-401;

In one embodiment, the additional appropriate therapeutic agents areselected from V-116517, Pregabalin, controlled release Pregabalin,Ezogabine (Potiga®). Ketamine/amitriptyline topical cream (Amiket®),AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine(Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 orARC-4558.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. The amount of additional therapeutic agent in thepresently disclosed compositions will range from about 10% to 100% ofthe amount normally present in a composition comprising that agent asthe only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, theinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the invention as describedgenerally above, and in classes and subclasses herein, and a carriersuitable for coating said implantable device. In still another aspect,the invention includes an implantable device coated with a compositioncomprising a compound of the invention as described generally above, andin classes and subclasses herein, and a carrier suitable for coatingsaid implantable device. Suitable coatings and the general preparationof coated implantable devices are described in U.S. Pat. Nos. 6,099,562;5,886,026; and 5,304,121. The coatings are typically biocompatiblepolymeric materials such as a hydrogel polymer, polymethyldisiloxane,polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinylacetate, and mixtures thereof. The coatings may optionally be furthercovered by a suitable topcoat of fluorosilicone, polysaccarides,polyethylene glycol, phospholipids or combinations thereof to impartcontrolled release characteristics in the composition.

Another aspect of the invention relates to inhibiting Na_(v)1.8 activityin a biological sample or a subject, which method comprisesadministering to the subject, or contacting said biological sample witha compound of formula I or a composition comprising said compound. Theterm “biological sample,” as used herein, includes, without limitation,cell cultures or extracts thereof; biopsied material obtained from amammal or extracts thereof; and blood, saliva, urine, feces, semen,tears, or other body fluids or extracts thereof.

Inhibition of Na_(v)1.8 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumchannels in biological and pathological phenomena; and the comparativeevaluation of new sodium channel inhibitors.

SCHEMES AND EXAMPLES

The following definitions describe terms and abbreviations used herein:

-   Ac acetyl-   Bu butyl-   Et ethyl-   Ph phenyl-   Me methyl-   THF tetrahydrofuran-   DCM dichloromethane-   CH₂Cl₂ dichloromethane-   EtOAc ethyl acetate-   CH₃CN acetonitrile-   MeCN acetonitrile-   ACN acetonitrile-   EtOH ethanol-   Et₂O diethyl ether-   MeOH methanol-   i-PrOH isopropyl alcohol-   MTBE methyl tert-butyl ether-   DMF N,N-dimethylformamide-   DMA N,N-dimethylacetamide-   DMSO dimethyl sulfoxide-   HOAc acetic acid-   NMP N-methylpyrrolidinone-   TEA triethylamine-   TFA trifluoroacetic acid-   TFAA trifluoroacetic anhydride-   Et₃N or NEt₃ triethylamine-   DIPEA or DIEA diisopropylethylamine-   K₂CO₃ potassium carbonate-   Na₂CO₃ sodium carbonate-   Na₂S₂O₃ sodium thiosulfate-   Cs₂CO₃ cesium carbonate-   NaHCO₃ sodium bicarbonate-   NaOH sodium hydroxide-   Na₂SO₄ sodium sulfate-   MgSO₄, magnesium sulfate-   K₃PO₄ potassium phosphate-   NH₄Cl ammonium chloride-   SO₂Cl₂ thionyl chloride-   KMnO₄ potassium permanganate-   DMAP N,N-dimethylaminopyridine-   HATU    1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidhexafluorophosphate-   EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   HOBT 1-hydroxybenzotriazole hydrate-   HCl hydrochloric acid-   H₂O water-   Pd/C palladium on carbon-   NaOAc sodium acetate-   H₂SO₄ sulfuric acid-   N₂ nitrogen gas-   H₂ hydrogen gas-   n-BuLi n-butyl lithium-   Pd(OAc)₂ palladium(II)acetate-   PPh₃ triphenylphosphine-   NBS N-bromosuccinimide-   Pd[(Ph₃)P]₄ tetrakis(triphenylphosphine)palladium(0)-   LC/MS liquid chromatography/mass spectra-   GCMS gas chromatography mass spectra-   HPLC high performance liquid chromatography-   GC gas chromatography-   LC liquid chromatography-   IC ion chromatography-   Hr or h hours-   min minutes-   atm atmospheres-   rt or RT room temperature-   TLC thin layer chromatography-   SM starting material-   Equiv. or Eq. equivalents-   aq aqueous-   N normal-   L liters-   mL milliliters-   μt microliters-   M molar-   μM micromolar-   nM nanomolar-   N normal-   mol moles-   mmol millimoles-   g grams-   mg milligrams-   μg micrograms-   ¹H-NMR proton nuclear magnetic resonance-   MHz megahertz-   Hz hertz-   CDCl₃ deutero chloroform-   DMSO-d6 deutero dimethyl sulfoxide-   MeOD deutero methanol-   CD₃OD deutero methanol-   K_(i) dissociation constant-   IC₅₀ half maximal inhibitory concentration

The compounds of the invention may be prepared readily using thefollowing methods. Illustrated below in Schemes 1-3 are general methodsfor preparing the compounds of the present invention.

Scheme 3 above may be used to insert a variety of R¹, R², R³ and R⁴groups starting with the aryl bromide. The scheme above shows thepresence of, for instance, an R¹ group and an aryl bromide which isreacted with a suitable boronic acid under Suzuki type conditions toreplace the bromide group with an R³ moiety. One of skill in the artwould recognize that a variety of R¹ through R⁴ groups could be insertedfrom the starting aryl bromide through this procedure.

EXAMPLES General Methods

¹H NMR (400 MHz) spectra were obtained as solutions in an appropriatedeuterated solvent such as dimethyl sulfoxide-d₆ (DMSO). Mass spectra(MS) were obtained using an Applied Biosystems API EX LC/MS system.Compound purity and retention times were determined by reverse phaseHPLC using a Kinetix C18 column (50×2.1 mm, 1.7 μm particle) fromPhenomenex (pn: 00B-4475-AN)), and a dual gradient run from 1-99% mobilephase B over 3 minutes. Mobile phase A=H₂O (0.05% CF₃CO₂H). Mobile phaseB=CH₃CN (0.05% CF₃CO₂H). Flow rate=2 mL/min, injection volume=3 μL, andcolumn temperature=50° C. Silica gel chromatography was performed usingsilica gel-60 with a particle size of 230-400 mesh. Pyridine,dichloromethane, tetrahydrofuran, dimethylformamide, acetonitrile,methanol, 1,4-dioxane and other commonly used solvents were from, forexample, Baker or Aldrich and in some cases the reagents were AldrichSure-Seal bottles kept under dry nitrogen. All reactions were stirredmagnetically unless otherwise noted.

Example 1 Preparation of2-fluoro-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide

To a solution of 3-aminobenzenesulfonamide (18.77 g, 109.0 mmol) andpyridine (88.16 mL, 1.090 mol) in dichloromethane (247.0 mL) at 0° C.was added dropwise 2-fluoro-5-(trifluoromethyl)benzoyl chloride (24.7 g,109.0 mmol). The mixture was allowed to warm to room temperature and wasstirred for 18 hours. The reaction mixture was diluted withdichloromethane and water. The layers were separated and the organiclayer washed with aqueous 1N HCl (2×). The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was triturated with dichloromethane and filtered. The whitesolid was washed with diethyl ether and was collected via vacuumfiltration to give2-fluoro-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide (23.83 g,60%) as a white solid. ESI-MS m/z calc. 362.03. found 363.3 (M+1)⁺;Retention time: 1.37 minutes (3 min run). ¹H NMR (400 MHz, DMSO-d₆) δ10.91 (s, 1H), 8.30 (s, 1H), 8.15-8.07 (m, 1H), 8.06-7.97 (m, 1H),7.89-7.83 (m, 1H), 7.64 (t, J=9.2 Hz, 1H), 7.62-7.54 (m, 2H), 7.42 (s,2H) ppm.

Example 2 Preparation of2-fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide

To a solution of 3-aminobenzenesulfonamide (3.8 g, 22.07 mmol) and2-fluoro-4-(trifluoromethyl)benzoyl chloride (5 g, 22.07 mmol) indichloromethane (90 mL) was added pyridine (10.7 mL, 132.4 mmol) and themixture was stirred at room temperature for 15 hours. Water (50 mL) wasadded to the reaction and the product crashed out. The solid wasisolated by filtration, washed with water (2×75 mL), and dried undervacuum to yield2-fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide (4.43 g) asa cream solid. The solvent was evaporated under reduced pressure. Waterwas added and the mixture was set aside. After a few minutes, solidprecipitated. The solid was isolated by filtration, washed with water(2×30 mL), and dried under vacuum to yield a second crop of the desiredproduct (2.7 g). The two crops were combined to yield2-fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide (7.13 g,88%) as a solid. ESI-MS m/z calc. 362.03. found 363.3 (M+1)⁺; Retentiontime: 1.63 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d₆) δ 10.93(s, 1H), 8.35-8.27 (m, 1H), 7.99-7.88 (m, 2H), 7.88-7.80 (m, 1H), 7.76(d, J=8.0 Hz, 1H), 7.65-7.51 (m, 2H), 7.43 (s, 2H) ppm.

Example 3 Preparation of4-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide

Pyridine (939.0 μL, 11.61 mmol) was added slowly to a solution of4-chloro-2-fluoro-benzoyl chloride (1.1 g, 5.81 mmol) and3-aminobenzenesulfonamide (1 g, 5.81 mmol) in dichloromethane (5 mL).The reaction was stirred at room temperature for 1 hour. The reactionmixture was filtered and the precipitate was washed with dichloromethaneand water to give 4-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide (1.8g, 92.2%) as a white solid. ESI-MS m/z calc. 328.01. found 329.1 (M+1)⁺;Retention time: 1.47 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d₆)δ 10.78 (s, 1H), 8.31 (s, 1H), 7.84 (d, J=6.8 Hz, 1H), 7.74 (t, J=8.0Hz, 1H), 7.66 (dd, J=10.0, 1.9 Hz, 1H), 7.57 (m, 2H), 7.46 (dd, J=8.3,1.9 Hz, 1H), 7.41 (s, 2H) ppm.

Example 4 Preparation of5-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide

A mixture of 5-chloro-2-fluoro-benzoic acid (349.1 mg, 2.0 mmol),3-aminobenzenesulfonamide (413.3 mg, 2.4 mmol), HATU (608.4 mg, 1.6mmol), and N-methylmorpholine (439.8 μL, 4.0 mmol) in DMF (4 mL) wasstirred at 40° C. for 1 hour. The reaction mixture was poured intowater, the pH was adjusted to 4, and the mixture was extracted withethyl acetate (3×). The organics were combined, washed with water,brine, dried over Na₂SO₄, filtered and evaporated to dryness to give5-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide (0.36 g, 55%) as anpale yellow solid. ESI-MS m/z calc. 328.01. found 329.1 (M+1)⁺;Retention time: 1.41 minutes (3 minutes run).

Example 5 Preparation of2-fluoro-4-methyl-N-(3-sulfamoylphenyl)benzamide

Pyridine (1.0 mL, 12.98 mmol) was added dropwise to a mixture of2-fluoro-4-methyl-benzoyl chloride (2.24 g, 12.98 mmol),3-aminobenzenesulfonamide (2.235 g, 12.98 mmol) and dichloromethane(40.32 mL) at room temperature. The mixture was allowed to stir at roomtemperature for 2.5 hours before water (150 mL) was added. The mixturewas filtered and the solid was collected by vacuum filtration. The solidwas slurried with diethyl ether (30 mL) and filtered (twice). The solidwas placed in a vacuum oven at 40° C. overnight to give2-fluoro-4-methyl-N-(3-sulfamoylphenyl)benzamide (1.81 g, 45%) as anoff-white solid. ESI-MS m/z calc. 308.06. found 309.5 (M+1)⁺; Retentiontime: 1.42 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d₆) δ 10.61(s, 1H), 8.32 (s, 1H), 7.89-7.80 (m, 1H), 7.62-7.51 (m, 3H), 7.39 (s,2H), 7.24-7.11 (m, 2H), 2.39 (s, 3H) ppm.

Example 6 Preparation of 4-cyano-2-fluoro-N-(3-sulfamoylphenyl)benzamide

A solution of 4-cyano-2-fluoro-benzoic acid (495.4 mg, 3.0 mmol),3-aminobenzenesulfonamide (516.6 mg, 3.0 mmol), EDCI (575.1 mg, 3.0mmol), HOBT (405.4 mg, 3.0 mmol) and N-methylmorpholine (659.7 μL, 6.0mmol) in DMF (4 mL) was stirred at 25° C. for 16 hours. The reactionmixture was poured into 1N HCl and extracted with ethyl acetate (3×).The organics were combined and washed with 1N HCl (3×), water, brine,dried over Na₂SO₄, filtered through a short plug of silica andevaporated to dryness to yield4-cyano-2-fluoro-N-(3-sulfamoylphenyl)benzamide (860 mg, 90%) as a whitesolid that was used in the next steps without further purification.ESI-MS m/z calc. 319.04. found 320.1 (M+1)⁺; Retention time: 1.04minutes (3 minutes run).

Example 7 Preparation of 5-cyano-2-fluoro-N-(3-sulfamoylphenyl)benzamide

A solution of 5-cyano-2-fluoro-benzoic acid (165.1 mg, 1.0 mmol),3-aminobenzenesulfonamide (206.6 mg, 1.20 mmol), HATU (342.2 mg, 0.90mmol) and N-methylmorpholine (219.9 μL, 2.0 mmol) in DMF (2 mL) wasstirred at 25° C. for 4 hours. The reaction mixture was poured intowater and extracted with ethyl acetate (3×). The organics were combined,washed with water, acidified to pH˜4 with 1N HCl and extracted withethyl acetate (3×). The organics were combined, washed with water,brine, dried with Na₂SO₄, filtered and evaporated to dryness to give5-cyano-2-fluoro-N-(3-sulfamoylphenyl)benzamide (150 mg, 47%) that wasused in the next steps without further purification. ESI-MS m/z calc.319.04. found 320.1 (M+1)+; Retention time: 0.97 minutes (3 minutesrun).

Example 8 Preparation of 2,4-difluoro-N-(3-sulfamoylphenyl)benzamide

To a mixture of 2,4-difluorobenzoyl chloride (2.0 g, 11.33 mmol),3-aminobenzenesulfonamide (1.95 g, 11.33 mmol) and dichloromethane (36.0mL) was added pyridine (3.7 mL, 45.32 mmol) at 25° C. The mixture wasallowed to stir at 25° C. for 18 h before it was washed with 1N HCl andwater. The organic layer was dried over sodium sulfate, filtered andconcentrated. The residue was subjected to column chromatography (0-100%ethyl acetate/hexanes) to give2,4-difluoro-N-(3-sulfamoylphenyl)benzamide (2.0 g, 57%). ESI-MS m/zcalc. 312.04. found 313.1 (M+1)⁺; Retention time: 1.31 minutes (3minutes run). ¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H), 8.31 (s, 1H),7.89-7.74 (m, 2H), 7.62-7.52 (m, 2H), 7.51-7.42 (m, 1H), 7.41 (s, 2H),7.26 (td, J=8.4, 2.2 Hz, 1H) ppm.

Example 9 Preparation of 2,5-difluoro-N-(3-sulfamoylphenyl)benzamide

To a solution of 3-aminobenzenesulfonamide (1.0 g, 5.81 mmol) andpyridine (4.7 mL, 58.07 mmol) in dichloromethane (10.3 mL) at 0° C. wasadded dropwise 2,5-difluorobenzoyl chloride (719.3 μL, 5.81 mmol). Themixture was allowed to warm to 25° C. and was stirred for 72 hours. Thereaction mixture was diluted with ethyl acetate and water. The layerswere separated and the organic layer washed with brine (2×). The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure to give a clear oil that crystallized upon standing.The solid was re-dissolved in ethyl acetate and washed with 1N HCl (3×).The organic layer was dried with MgSO₄, filtered and evaporated to yield2,5-difluoro-N-(3-sulfamoylphenyl)benzamide (1.17 g, 64%) as a whitesolid. ESI-MS m/z calc. 312.04. found 313.3 (M+1)⁺; Retention time: 1.31minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 1H), 8.31(s, 1H), 7.84 (d, J=9.1 Hz, 1H), 7.59-7.54 (m, 3H), 7.50-7.39 (m, 4H)ppm.

Example 10 Preparation of2,5-difluoro-4-methyl-N-(3-sulfamoylphenyl)benzamide

A solution of 3-aminobenzenesulfonamide (413.3 mg, 2.40 mmol),2,5-difluoro-4-methyl-benzoic acid (344.3 mg, 2.0 mmol), HATU (684.4 mg,1.80 mmol) and N-methylmorpholine (439.8 μL, 4.0 mmol) in DMF (2 mL) wasstirred at 40° C. for 2 hours. The reaction was poured into 1N HCl andextracted with ethyl acetate (3×). The organics were combined, washedwith water, brine, dried with Na₂SO₄ and evaporated to dryness to give2,5-difluoro-4-methyl-N-(3-sulfamoylphenyl)benzamide (610 mg, 94%) as asolid that was used in the next step without further purification.ESI-MS m/z calc. 326.05. found 327.3 (M+1)⁺; Retention time: 1.25minutes (3 minutes run).

Example 11 Preparation of2-fluoro-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide

To a solution of 3-aminobenzenesulfonamide (760.1 mg, 4.41 mmol) indichloromethane (10 mL) was added 2-fluoro-6-(trifluoromethyl)benzoylchloride (1 g, 4.41 mmol), 3-aminobenzenesulfonamide (760.1 mg, 4.41mmol) and pyridine (1.1 mL, 13.24 mmol) and the mixture was stirred at25° C. for 12 hours. The reaction was diluted with dichloromethane andwater. The 2 layers were separated and the organic layer washed withwater and 1N HCl. The organics were combined and evaporated to yield2-fluoro-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide (600 mg,37%) as a light pink solid. ESI-MS m/z calc. 362.03. found 363.3 (M+1)⁺;Retention time: 1.39 minutes (3 minutes run). ¹H NMR (400 MHz, CD₃CN) δ9.18 (s, 1H), 8.31 (t, J=1.9 Hz, 1H), 7.83-7.43 (m, 6H), 5.75 (s, 2H)ppm.

Example 12 Preparation of 5-(difluoromethyl)-2-fluorobenzoic acid

2-Fluoro-5-methyl-benzoic acid (2 g, 12.98 mmol), NBS (6.0 g, 33.75mmol) and benzoyl peroxide (157.2 mg, 0.65 mmol) in CCl₄ (30 mL) washeated at reflux for 48 hours. The solids were filtered off and washedwith dichloromethane. The solvent was evaporated and the residue wastaken up in ethanol (30 mL) and heated to 50° C. A solution of silvernitrate (2.20 g, 12.98 mmol) in 5 ml water was added drop wise. Themixture was stirred for 45 minutes, cooled to 25° C., then poured into1N HCl. The solids were filtered off and washed with EtOH. The EtOH wasremoved and the aqueous layer was extracted with ethyl acetate (3×). Theorganics were combined, washed with brine, dried over Na₂SO₄ andevaporated to dryness. Purification by column chromatography using agradient of ethyl acetate in hexanes (0-50%) gave2-fluoro-5-formyl-benzoic acid (0.33 g, 15%) as a light yellow solid.ESI-MS m/z calc. 168.02. found 169.1 (M+1)⁺; Retention time: 0.49minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d₆) δ 13.64 (s, 1H),10.03 (s, 1H), 8.43 (dd, J=7.2, 2.2 Hz, 1H), 8.17 (ddd, J=8.4, 4.7, 2.2Hz, 1H), 7.56 (dd, J=10.6, 8.6 Hz, 1H) ppm.

Deoxofluor (566.8 μL, 3.07 mmol) was added to methyl2-fluoro-5-formyl-benzoate (280 mg, 1.54 mmol) followed by 2 drops ofethanol and the reaction mixture was stirred at 25° C. for 4 hours. Moredeoxofluor (100 μL, 0.54 mmol) was added and the reaction mixture wasstirred for an additional hour. The mixture was carefully quenched withsaturated aqueous solution of sodium bicarbonate and then extracted withethyl acetate (3×). The organics were combined, washed with water,brine, dried over Na₂SO₄, filtered and evaporated to dryness.Purification by column chromatography using a gradient of ethyl acetatein hexanes (0-20%) gave methyl 5-(difluoromethyl)-2-fluoro-benzoate (230mg, 73%) as a clear oil. ESI-MS m/z calc. 204.04. found 204.9 (M+1)⁺;Retention time: 1.31 minutes (3 minutes run). ¹H NMR (400 MHz, CDCl₃) δ8.26-8.05 (m, 1H), 7.81-7.58 (m, 1H), 7.29-7.19 (m, 1H), 6.66 (t, J=56.1Hz, 1H), 3.96 (s, 3H) ppm.

To a solution of methyl 5-(difluoromethyl)-2-fluoro-benzoate (230 mg,1.127 mmol) in THF (4 mL) was added a solution of LiOH (269.9 mg, 11.27mmol) in water (1 mL) and the reaction mixture was stirred at 25° C. for4 hours. The reaction was brought to pH 4 with 4N HCl and then extractedwith ethyl acetate (3×). The organics were combined, washed with water,brine, dried over Na₂SO₄, filtered and evaporated to dryness to give5-(difluoromethyl)-2-fluoro-benzoic acid (187 mg, 87%) as a white solid.ESI-MS m/z calc. 190.02. found 191.3 (M+1)⁺; Retention time: 1.0 minutes(3 minutes run).

Example 13 Preparation of5-(difluoromethyl)-2-fluoro-N-(3-sulfamoylphenyl)benzamide

To a solution of 5-(difluoromethyl)-2-fluoro-benzoic acid (95.1 mg, 0.50mmol), 3-aminobenzenesulfonamide (94.7 mg, 0.55 mmol), andN-methylmorpholine (109.9 μL, 1.0 mmol) in DMF (1 mL) was added HATU(209 mg, 0.55 mmol) and the reaction mixture was stirred at 25° C. for 1hour. The reaction was poured into 1N HCl and extracted with ethylacetate (3×). The organics were combined, washed with water (2×), brine,dried with Na₂SO₄, filtered and evaporated to dryness. Purification bysilica gel column chromatography using a 20-80% gradient of ethylacetate in hexanes gave5-(difluoromethyl)-2-fluoro-N-(3-sulfamoylphenyl)benzamide (202mg, >100%) that was used in the next step without further purification.ESI-MS m/z calc. 344.04. found 345.3 (M+1)⁺; Retention time: 1.19minutes (3 minutes run).

Example 14 Preparation of5-bromo-4-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide

To 5-bromo-4-chloro-2-fluoro-benzoic acid (5.0 g, 19.73 mmol),3-aminobenzenesulfonamide (5.1 g, 29.60 mmol), 1-hydroxybenzotriazole(2.93 g, 21.70 mmol),3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride(4.2 g, 21.70 mmol), and N,N-dimethylformamide (80 mL), triethyl amine(5.5 mL, 39.46 mmol) was added and stirred at room temperature for 18hours. The solvent was evaporated. The reaction was washed with a 1Msolution of hydrochloric acid (3×50 mL), a saturated aqueous solution ofsodium bicarbonate (3×50 mL), and a saturated aqueous solution of sodiumchloride (3×50 mL). The organic layer was dried over sodium sulfate,filtered, and evaporated to dryness. The crude product was dissolved indichloromethane and the precipitate was isolated by filtration to yield5-bromo-4-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide (4.0 g, 35%) asa grey solid. The product was used in the next step without furtherpurification. ESI-MS m/z calc. 405.92. found 407.0 (M+1)+; Retentiontime: 1.7 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s,1H), 8.32-8.24 (m, 1H), 8.13 (d, J=7.0 Hz, 1H), 7.90 (d, J=9.7 Hz, 1H),7.86-7.81 (m, 1H), 7.61-7.53 (m, 2H), 7.42 (s, 2H) ppm.

Example 15 Preparation of2-fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide

To 2-fluoro-4-(trifluoromethoxy)benzoic acid (5 g, 22.31 mmol) inthionyl chloride (2.43 mL, 33.46 mmol) was added N,N-dimethylformamide(491.6 μL, 6.38 mmol). The reaction mixture was stirred at roomtemperature for 17 hours. Excess thionyl chloride and N,N-dimethylformamide were removed in vacuo to yield2-fluoro-4-(trifluoromethoxy)benzoyl chloride that was used in the nextstep without further purification.

To 3-aminobenzenesulfonamide (4.79 g, 27.83 mmol) was added potassiumcarbonate (3.85 g, 27.82 mmol), methyl tert-butyl ether (27.0 mL) andwater (27.0 mL). The reaction was cooled to 0° C. To the vigorouslystirred reaction was added 2-fluoro-4-(trifluoromethoxy)benzoyl chloride(5.4 g, 22.26 mmol) in dichloromethane (13.5 mL). The reaction wasstirred at room temperature for 30 hours. The reaction was a slurry. Theproduct was isolated by filtration using ether. The product was loadedonto celite and purified by silica gel chromatography utilizing agradient of 0-50% ethyl acetate in dichloromethane to yield 3 g (35%) of2-fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide. ¹H NMR(400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.38-8.25 (m, 1H), 7.90-7.78 (m,2H), 7.66-7.52 (m, 3H), 7.47-7.36 (m, 3H) ppm. ESI-MS m/z calc. 378.03.found 379.4 (M+1)+; Retention time: 1.56 minutes (3 minutes run).

Example 16 Preparation of2-fluoro-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide

To a stirred solution of 4-bromo-2-fluoro-benzoic acid (3.0 g, 13.70mmol) and copper (8.70 g, 137.0 mmol) in DMSO (56.3 mL) in a bomb,1,1,1,2,2-pentafluoro-2-iodo-ethane (23.6 g, 95.90 mmol) was bubbledthrough. The vessel was sealed and heated at 120° C. for 72 hours. Thereaction mixture was diluted with water and filtered through a plug ofsilica and then extracted with ethyl acetate (4×). The organics werecombined, washed with brine, dried (Na₂SO₄) and evaporated to dryness.Purification by column chromatography using a gradient of 0-40% ethylacetate in hexanes gave 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoicacid (1.81 g, 51%) as white solid. ESI-MS m/z calc. 258.01. found 259.3(M+1)+; Retention time: 1.45 minutes.

A solution of 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoic acid (516.2mg, 2.0 mmol), 3-aminobenzenesulfonamide (378.9 mg, 2.20 mmol), HATU(836.5 mg, 2.20 mmol) and N-methylmorpholine (439.8 μL, 4.0 mmol) in DMF(6 mL) was stirred at room temperature for 16 hours. The reactionmixture was poured into water, the pH adjusted to 4 with 1N HCl andextracted with ethyl acetate (3×). The organics were combined, washedwith water, brine, dried over Na₂SO₄ and evaporated to dryness.Purification by column chromatography using a gradient of 0-50% ethylacetate in hexanes gave2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)-N-(3-sulfamoylphenyl)benzamide(710 mg, 86%) as a white solid. ESI-MS m/z calc. 412.03165. found 413.3(M+1)+; Retention time: 1.5 minutes.

Example 17 Preparation of4,5-dichloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide

A solution of 3-aminobenzenesulfonamide (271.9 mg, 1.58 mmol),4,5-dichloro-2-fluoro-benzoic acid (300 mg, 1.43 mmol), and HATU (654.8mg, 1.72 mmol) in DMF (3.12 mL) was treated with N-methylmorpholine(315.5 μL, 2.87 mmol) and stirred at 40° C. for 16 hours. The reactionwas diluted with ethyl acetate and water and the organic layerseparated. The organic layer was washed with 1 N HCl, water (3×50 mL),and brine, then dried over Na₂SO₄, filtered, and concentrated. Theresidue was slurried in dichloromethane to form a white precipitate. Theprecipitate was filtered and washed with dichloromethane to provide4,5-dichloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide (422 mg, 81%) as awhite powder. ¹H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.32-8.25 (m,1H), 8.03 (d, J=6.7 Hz, 1H), 7.93 (d, J=9.5 Hz, 1H), 7.83 (dt, J=6.8,2.2 Hz, 1H), 7.64-7.52 (m, 2H), 7.42 (s, 2H) ppm. ESI-MS m/z calc.361.96948. found 364.7 (M+1)+; Retention time: 1.4 minutes (3 minutesrun).

Example 18 Preparation of2-fluoro-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide

To 3-aminobenzenesulfonamide (300.8 mg, 1.75 mmol) inmethyl-tert-butylether (2.8 mL) was added K₂CO₃ (689.9 mg, 5.0 mmol) inwater (2.8 mL). The reaction was stirred at room temperature and2-fluoro-4,6-bis(trifluoromethyl)benzoyl chloride (490 mg, 1.66 mmol) inmethyl-tert-butylether (2.8 mL) was added dropwise. The reaction wasstirred at room temperature for 40 minutes. Ethyl acetate (50 ml) wasadded and the organic layer was separated, washed with brine, andconcentrated to yield2-fluoro-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide (162mg, 23%) as a pink solid that was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.49-8.35 (m,1H), 8.31-8.08 (m, 2H), 7.74 (dt, J=7.5, 1.9 Hz, 1H), 7.69-7.54 (m, 2H),7.46 (s, 2H) ppm.

Example 19 Preparation of2,4-dichloro-6-fluoro-N-(3-sulfamoylphenyl)benzamide

To a solution of 2,4-dichloro-6-fluoro-benzoic acid (400 mg, 1.91 mmol),3-aminobenzenesulfonamide (329.6 mg, 1.91 mmol), and HATU (727.8 mg,1.91 mmol) in DMF (4 mL) was added N-methylmorpholine (210.4 μL, 1.91mmol) and the reaction mixture was stirred at room temperature for 16hours. The reaction mixture was poured into 1N HCl and extracted withethyl acetate (3×). The organics were combined, washed with 1N HCl,water, brine, dried over Na₂SO₄, filtered and evaporated to dryness.Purification by column chromatography using a gradient of ethyl acetatein hexanes 1-50% gave2,4-dichloro-6-fluoro-N-(3-sulfamoylphenyl)benzamide (420 mg, 60%) as awhite solid.

Example 20 Preparation of2-cyclopropyl-6-fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide

To a mixture of 2,6-difluoro-4-(trifluoromethyl)benzoic acid (500 mg,2.21 mmol) in THF (4.0 mL) was slowly added bromo(cyclopropyl)magnesium(12.0 mL of 0.5 M, 6.00 mmol). The reaction was stirred at roomtemperature for one hour then at 55° C. for one hour. To the reactionwas added additional bromo(cyclopropyl)magnesium (8.84 mL of 0.5 M, 4.42mmol) and the reaction was stirred at 55° C. for 12 additional hours.The reaction mixture was carefully poured into 50 ml of saturated NH₄Cland was extracted with ethyl acetate. The organic layer was washed withwater. The combined water layers were acidified to pH=3 using 1N HCl andwere extracted with ethyl acetate (2×50 ml), dried over sodium sulfate,filtered and concentrated to provide2-cyclopropyl-6-fluoro-4-(trifluoromethyl)benzoic acid (345 mg, 63%)that was used in the next step without further purification. ESI-MS m/zcalc. 248.05. found 249.15 (M+1)+; Retention time: 0.59 minutes (1minute run). ¹H NMR (400 MHz, DMSO-d6) δ 7.91-7.43 (m, 1H), 7.12 (s,1H), 2.04 (tt, J=8.4, 5.2 Hz, 1H), 1.09-0.98 (m, 2H), 0.89-0.80 (m, 2H)ppm.

2-Cyclopropyl-6-fluoro-4-(trifluoromethyl)benzoic acid (345 mg, 1.39mmol), toluene (3.4 mL) and pyridine (5.6 μL, 0.069 mmol) were added toa reaction vessel and the mixture was heated to 60° C. under an inertatmosphere. To the reaction mixture was added SOCl₂ (202.8 μL, 2.780mmol) and the mixture was stirred for 90 minutes. Additional SOCl₂ (900μl, 12.34 mmol) was added and the mixture was concentrated in vacuo.Toluene was added and the mixture concentrated again to give a productthat was used in the next step without further purification.

To 3-aminobenzenesulfonamide (271.4 mg, 1.576 mmol) in methyl-t-butylether (1.99 mL) and DMF (1 mL) was added K₂CO₃ (544.4 mg, 3.94 mmol) inwater (1.99 mL). The reaction was stirred at room temperature and2-cyclopropyl-6-fluoro-4-(trifluoromethyl)benzoyl chloride (350 mg, 1.31mmol) in methyl-t-butyl ether (1.99 mL) was added dropwise. The reactionwas stirred at room temperature overnight after which 50 ml of ethylacetate were added. The 2 layers were separated and the organic layerwas washed with brine, dried with MgSO₄, filtered and concentrated toyield2-cyclopropyl-6-fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide(220 mg, 42%) as a pink solid that was used in the next step withoutfurther purification. ESI-MS m/z calc. 402.07. found 403.1 (M+1)+;Retention time: 0.59 minutes (1 minute run).

Example 21 Preparation of2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide(33)

To a solution of 2-chloro-4-fluoro-phenol (21 g, 143.1 mmol) and2-fluoro-6-(trifluoromethyl)benzaldehyde (25 g, 130.1 mmol) in DMF(125.0 mL) was added Cs₂CO₃ (46.6 g, 143.1 mmol) and the reactionmixture was stirred at 100° C. for 1 hour. The mixture was poured intowater (500 ml) and extracted with ethyl acetate (3×150 ml). The organicswere combined, washed with water, brine (2×), dried over Na₂SO₄,filtered and evaporated to give a red oil that solidified after standingover night. The material was then triturated with hot hexanes and cooledto 25° C. The slurry was filtered and washed with cold hexanes to give2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde (32.7 g,79%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.61 (s, 1H),7.84-7.70 (m, 2H), 7.66 (d, J=7.9 Hz, 1H), 7.47 (dd, J=9.0, 5.3 Hz, 1H),7.42-7.32 (m, 1H), 7.12 (d, J=8.3 Hz, 1H) ppm.

To a solution of2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde (31 g,97.3 mmol) in tBuOH (155.0 mL), water (100.8 mL), CH₃CN (155.0 mL) and2-methyl-2-butene (51.45 mL, 486.4 mmol) was added sodium dihydrogenphosphate (18.3 mL, 291.9 mmol) and the mixture was cooled to 0° C.Sodium chlorite (26.40 g, 291.9 mmol) was added in one portion and themixture was stirred at 25° C. for 1 hour. The pH of the mixture wasadjusted to 2-3 with 1N HCl and the layers separated. The aqueous wasextracted with ethyl acetate (3λ). All organic layers were combined, andin the separatory funnel, solid sodium sulfite (˜5 g) was added followedby brine (50 ml) and 1N NaOH (10 ml) and the mixture was shaken untilthe yellow color was gone. The layers were separated and the organic waswashed with brine, dried with Na₂SO₄, filtered through a short plug ofsilica gel and evaporated to dryness to give2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoic acid (40 g,98%) as an oil that was used in the next step without furtherpurification. ESI-MS m/z calc. 334.00. found 335.1 (M+1)⁺; Retentiontime: 1.78 minutes (3 minutes run).

To a stirred solution of2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoic acid (20 g,47.81 mmol) in NMP (110 mL) was added HATU (16.36 g, 43.03 mmol)followed by 3-aminobenzenesulfonamide (9.88 g, 57.37 mmol) andN-methylmorpholine (10.51 mL, 95.60 mmol) and the mixture was heated to80° C. and stirred at this temperature for 4 hours. The reaction wasrecharged with 3-aminobenzenesulfonamide (4.12 g, 23.91 mmol) wasstirred at 80° C. for 13 hours. The mixture was poured into 1N HCl (400ml) and extracted with ethyl acetate (3×200 ml). The organics werecombined, washed with 1N HCl (2×400 ml), water (2×400 ml), brine andthen dried with Na₂SO₄, filtered and evaporated to dryness to yield acrude mixture that was purified by silica gel column chromatographyusing a gradient of ethyl acetate and hexanes (0-50%) to give thedesired product as a white foam. After drying under vacuum,2-(2-chloro-4-fluoro-phenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide(33) (14 g, 60%) was obtained as a white solid. ESI-MS m/z calc. 488.02.found 489.3 (M+1)+; Retention time: 1.57 minutes (3 minutes run). ¹H NMR(400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 8.29 (s, 1H), 7.73 (d, J=7.3 Hz,1H), 7.69-7.60 (m, 3H), 7.59-7.51 (m, 2H), 7.41 (s, 2H), 7.38-7.29 (m,2H), 7.10 (d, J=7.3 Hz, 1H) ppm.

Example 22 Preparation of2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide(13)

2-Fluoro-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide (130 mg,0.36 mmol), 4-fluoro-2-methoxy-phenol (204.5 μL, 1.8 mmol) and Cs₂CO₃(584.5 mg, 1.8 mmol) in NMP (1 mL) was stirred at 90° C. for 4 hours.The reaction mixture was poured into 1N HCl and extracted with ethylacetate (3×). The organics were combined, washed with water, brine,dried with Na₂SO₄ and evaporated to dryness. Purification byreverse-phase HPLC using a gradient of (1-99% ACN in water (HClmodifier)) gave2-(4-fluoro-2-methoxy-phenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide(13) (25.6 mg, 14%) as a white solid. ESI-MS m/z calc. 484.07. found485.3 (M+1)+; Retention time: 1.61 minutes (3 minutes run). ¹H NMR (400MHz, DMSO-d₆) δ 10.98 (s, 1H), 8.33 (s, 1H), 7.79-7.72 (m, 1H),7.61-7.48 (m, 4H), 7.40 (s, 2H), 7.20 (dd, J=8.9, 5.9 Hz, 1H), 7.14 (dd,J=10.7, 2.9 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.84 (td, J=8.4, 2.8 Hz,1H), 3.77 (s, 3H) ppm.

Following a similar procedure as described above for compound (13), thefollowing compounds were prepared from2-fluoro-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide and aphenol.

Cmpd. No. Product name Phenol 12 2-(4-fluoro-2-methylphenoxy)-N-(3-4-fluoro-2-methylphenol sulfamoylphenyl)-6- (trifluoromethyl)benzamide57 2-(2-methoxyphenoxy)-N-(3- 2-methoxyphenol sulfamoylphenyl)-6-(trifluoromethyl)benzamide 58 2-(4-chloro-2-methylphenoxy)-N-(3-4-chloro-2-methylphenol sulfamoylphenyl)-6- (trifluoromethyl)benzamide59 2-(3-fluoro-2-methylphenoxy)-N-(3- 3-fluoro-2-methylphenolsulfamoylphenyl)-6- (trifluoromethyl)benzamide 60N-(3-sulfamoylphenyl)-2-(4- 4-(trifluoromethoxy)-(trifluoromethoxy)phenoxy)-6- phenol (trifluoromethyl)benzamide 612-(3-fluoro-4-methoxyphenoxy)-N- 3-fluoro-4- (3-sulfamoylphenyl)-6-methoxyphenol (trifluoromethyl)benzamide 74 2-(2-chlorophenoxy)-N-(3-2-chlorophenol sulfamoylphenyl)-6- (trifluoromethyl)benzamide 752-(2-chloro-4-methoxyphenoxy)-N- 2-chloro-4- (3-sulfamoylphenyl)-6-methoxyphenol (trifluoromethyl)benzamide

Example 23 Preparation of2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide(1)

2-Fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide (32.2 mg,0.1 mmol), 4-fluorophenol (112.1 mg, 1 mmol) were dissolved in DMF (1mL). Cs₂CO₃ (325.8 mg, 1 mmol) was added and the reactions was heated at100° C. for 1 hour. The reaction was filtered and purified by reversephase preparative HPLC utilizing a gradient of 10-99% acetonitrile inwater (HCl as a modifier) to yield2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide(1) (25.6 mg, 56%). ESI-MS m/z calc. 454.06. found 455.3 (M+1)+;Retention time: 1.96 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d₆)δ 10.84 (s, 1H), 8.34-8.24 (m, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.82-7.72(m, 1H), 7.64 (dd, J=7.9, 0.8 Hz, 1H), 7.60-7.47 (m, 2H), 7.40 (s, 2H),7.32-7.25 (m, 2H), 7.25-7.18 (m, 2H), 7.15 (s, 1H) ppm.

Following a similar procedure as described above for compound (1), thefollowing compounds were prepared starting from2-fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide and thefollowing phenols.

Cmpd. No. Product name Phenol 2 2-(2,4-difluorophenoxy)-N-(3-2,4-difluorophenol sulfamoylphenyl)-4- (trifluoromethyl)benzamide 142-(4-fluoro-2-methoxyphenoxy)-N- 4-fluoro-2-methoxyphenol(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 182-(4-fluoro-2-methylphenoxy)-N- 4-fluoro-2-methylphenol(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 422-(4-chloro-2-methoxyphenoxy)-N- 4-chloro-2-methoxyphenol(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 432-(3-fluoro-4-methoxyphenoxy)-N- 3-fluoro-4-methoxyphenol(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 442-(2-methoxyphenoxy)-N-(3- 2-methoxyphenol sulfamoylphenyl)-4-(trifluoromethyl)benzamide 45 2-(4-ethoxyphenoxy)-N-(3- 4-ethoxyphenolsulfamoylphenyl)-4- (trifluoromethyl)benzamide 462-(2-propoxyphenoxy)-N-(3- 2-(2-propoxy)phenol sulfamoylphenyl)-4-(trifluoromethyl)benzamide 47 N-(3-sulfamoylphenyl)-2-(o- 2-methylphenoltolyloxy)-4- (trifluoromethyl)benzamide 482-(2-chloro-4-methoxyphenoxy)- 2-chloro-4-methoxyphenolN-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 492-(4-methoxy-2-methylphenoxy)- 4-methoxy-2-methylphenolN-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 502-(2,4-dimethoxyphenoxy)-N-(3- 2,4-dimethoxyphenol sulfamoylphenyl)-4-(trifluoromethyl)benzamide 51 N-(3-sulfamoylphenyl)-2-(4-4-(trifluoromethoxy)phenol (trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide 52 2-(3-fluoro-2-methoxyphenoxy)-3-fluoro-2-methoxyphenol N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide 53 2-(4-isopropoxyphenoxy)-N-(3-4-isopropoxyphenol sulfamoylphenyl)-4- (trifluoromethyl)benzamide 672-(3-chloro-4-methoxyphenoxy)- 3-chloro-4-methoxyphenolN-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 682-(3-chloro-2-methoxyphenoxy)- 3-chloro-2-methoxyphenolN-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide 732-(2-chlorophenoxy)-N-(3- 2-chlorophenol sulfamoylphenyl)-4-(trifluoromethyl)benzamide

Example 24 Preparation of5-chloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide (5)

5-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide (32.8 mg, 0.1 mmol),4-fluorophenol (35.8 mg, 0.3 mmol) were dissolved in NMP (0.5 mL).Cs₂CO₃ (98 mg, 0.3 mmol) was added and the reactions was heated at 90°C. for 6 hour. The reaction was filtered and purified by reverse phasepreparative HPLC utilizing a gradient of 10-99% acetonitrile in water(HCl as a modifier) to yield5-chloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide (5) (10.2mg, 24%). ESI-MS m/z calc. 420.03. found 421.1 (M+1)+; Retention time:1.70 minutes (3 minutes run).

Following a similar procedure as described above for compound (5), thefollowing compounds were prepared.

Cmpd. No. Product name Aryl fluoride Phenol 16 5-chloro-2-(4-fluoro-2-5-chloro-2-fluoro-N-(3- 4-fluoro-2- methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide methoxyphenol sulfamoylphenyl)benzamide 175-chloro-2-(2-chloro-4- 5-chloro-2-fluoro-N-(3- 2-chloro-4-fluorophenoxy)-N-(3- sulfamoylphenyl)benzamide fluorophenolsulfamoylphenyl)benzamide 20 5-chloro-2-(4-fluoro-2-5-chloro-2-fluoro-N-(3- 4-fluoro-2- methylphenoxy)-N-(3-sulfamoylphenyl)benzamide methylphenol sulfamoylphenyl)benzamide

Example 25 Preparation of2-(2-chloro-4-fluorophenoxy)-6-methyl-N-(3-sulfamoylphenyl)benzamide(38)

To a solution of 2-fluoro-6-methyl-benzaldehyde (1.1 g, 7.75 mmol) and2-chloro-4-fluoro-phenol (817.7 μL, 7.75 mmol) in DMF (9.2 mL) was addedcesium carbonate (2.5 g, 7.75 mmol) and the mixture was heated at 100°C. for 1 hour. The mixture was cooled to room temperature before it wasdiluted with ethyl acetate and water. The layers were separated and theaqueous layer was extracted with ethyl acetate (3×). The combinedorganics were washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue was purified by column chromatography using agradient of ethyl acetate in hexanes (0-100%) to yield2-(2-chloro-4-fluoro-phenoxy)-6-methyl-benzaldehyde (1.05 g, 51%).ESI-MS m/z calc. 264.03. found 265.1 (M+1)+; Retention time: 2.02minutes (3 minutes run).

To a solution of 2-(2-chloro-4-fluoro-phenoxy)-6-methyl-benzaldehyde(1.05 g, 3.97 mmol) in t-BuOH (10.50 mL), water (6.6 mL) andacetonitrile (6.6 mL) was added sodium dihydrogen phosphate (745.7 μL,11.90 mmol), 2-methylbut-2-ene (2.1 mL, 19.83 mmol) and sodium chlorite(1.08 g, 11.90 mmol). The reaction mixture was stirred at 25° C. for 1h. The reaction mixture was acidified with 1N HCl and was diluted withethyl acetate. Sodium sulfite was added to remove the faint yellowcolor. The two layers were separated and the aqueous layer was extractedwith ethyl acetate (3×). The organics were combined, washed with brine,dried over sodium sulfate, filtered and concentrated to give2-(2-chloro-4-fluoro-phenoxy)-6-methyl-benzoic acid (1.06 g, 95%).ESI-MS m/z calc. 280.03. found 281.5 (M+1)+; Retention time: 1.7 minutes(3 minutes run).

DMF (1.4 μL, 0.018 mmol) was added to a mixture of2-(2-chloro-4-fluoro-phenoxy)-6-methyl-benzoic acid (100 mg, 0.36 mmol),CH₂Cl₂ (2.0 mL) and SOCl₂ (33.8 μL, 0.46 mmol) at room temperature. Themixture was allowed to stir for 1.5 hours before it was concentratedunder reduced pressure. The residue was placed under high vacuum for 30minutes before it was taken up in CH₂Cl₂ (2.0 mL) and added to a mixtureof 3-aminobenzenesulfonamide (92.0 mg, 0.53 mmol), Et₃N (86.5 μL, 1.07mmol) and CH₂Cl₂ (2.0 mL) at room temperature. The mixture was allowedto stir for 2 h at room temperature before it was partitioned between 1NHCl and CH₂Cl₂. The layers were separated and the organic layer waswashed with brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was subjected to preparatory-HPLC(10-90% ACN/water with 0.01% HCl) to give2-(2-chloro-4-fluoro-phenoxy)-6-methyl-N-(3-sulfamoylphenyl)benzamide(38) (6.5 mg, 4%). ESI-MS m/z calc. 434.05. found 435.5 (M+1)+;Retention time: 1.72 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d₆)δ 10.83 (s, 1H), 8.41-8.36 (m, 1H), 7.76 (dt, J=7.1, 2.0 Hz, 1H),7.63-7.51 (m, 3H), 7.39 (s, 2H), 7.34-7.25 (m, 3H), 7.12-7.07 (m, 1H),6.61 (t, J=8.0 Hz, 1H), 2.35 (s, 3H) ppm.

Example 26 Preparation of2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide(3)

A mixture of 2-fluoro-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide(9.0 g, 24.8 mmol), 4-fluorophenol (8.4 g, 74.5 mmol), cesium carbonate(24.3 g, 74.5 mmol) and DMF (225.0 mL) was heated at 100° C. for 0.5hours. The mixture was cooled to room temperature before it waspartitioned between ethyl acetate and water. The layers were separatedand the aqueous layer was extracted with ethyl acetate (3×). Thecombined organics were washed with saturated aqueous NH₄Cl, water andbrine. The organics were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (0-100% ethyl acetate/hexanes) to give an off-whitesolid. The solid was slurried with hexane, then filtered. That solid wasslurried in diethyl ether and filtered (2×). The solid was placed undervacuum at 55° C. for 1 hour to give2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide(3) (8.6 g, 77%). ESI-MS m/z calc. 454.06. found 455.5 (M+1)+; Retentiontime: 1.87 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d₆) δ 10.81(s, 1H), 8.30 (s, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.82 (ddd, J=8.9, 4.8,2.2 Hz, 2H), 7.61-7.49 (m, 2H), 7.40 (s, 2H), 7.35-7.23 (m, 4H), 7.00(d, J=8.7 Hz, 1H) ppm.

Example 27 Preparation of2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide(25)

To a mixture of2-fluoro-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide (10 g, 27.60mmol) in DMF (55.00 mL) was added 4-fluoro-2-methyl-phenol (3.7 g, 28.98mmol) and cesium carbonate (10.8 g, 33.12 mmol) and the mixture heatedat 100° C. for 1 h. The mixture was cooled to ambient temperature anddiluted with 300 mL of ice water. The mixture was acidified with 6N HCland diluted to a volume of 400 mL with water. The slurry was dilutedwith 400 mL of ethyl acetate and the organic phase separated. Theorganic phase was washed with 400 mL of water and then 400 mL of brine.The organic phase was dried over MgSO₄, filtered and concentrated invacuo. The crude solid was diluted with 100 mL of acetonitrile andheated until homogeneous. Mixture stirred at 25° C., the precipitate wascollected by filtration and washed with 25 mL of acetonitrile to yield2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide(25) (4.14 g, 32%). ESI-MS m/z calc. 468.08. found 469.20 (M+1)+;Retention time: 1.81 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d₆)δ 10.83 (s, 1H), 8.33 (s, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.81 (m, 2H),7.56 (m, 2H), 7.40 (s, 2H), 7.23 (ddd, J=13.9, 9.1, 4.0 Hz, 2H), 7.14(td, J=8.6, 3.1 Hz, 1H), 6.82 (d, J=8.7 Hz, 1H), 2.15 (s, 3H) ppm.

Example 28 Preparation of2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide(26)

A mixture of 2-fluoro-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide(15 g, 41.40 mmol), 2-chloro-4-fluoro-phenol (17.35 g, 118.4 mmol),cesium carbonate (40.47 g, 124.20 mmol) and DMF (375.0 mL) was heated at100° C. for 1 hour and 15 minutes. The mixture was cooled to roomtemperature and filtered using ethyl acetate. Water was added to thefiltrate. The layers were separated and the aqueous layer was extractedwith ethyl acetate (3×100 mL). The combined organics were washed withsaturated aqueous solution of NH₄Cl, water and brine. The organics weredried over sodium sulfate, filtered and concentrated under reducedpressure. The crude product was purified silica gel chromatographyutilizing a gradient of ethyl acetate in dichloromethane (0-10%). Thefractions containing the desired product were concentrated and theresulting solid slurried in ether and hexanes and filtered. The solventwas evaporated under reduced pressure to yield2-(2-chloro-4-fluoro-phenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide(26) (10.35 g, 50%) as a light pink solid. ESI-MS m/z calc. 488.02.found 489.2 (M+1)+; Retention time: 2.03 minutes (3 minutes run). ¹H NMR(400 MHz, DMSO-d₆) δ 10.83 (s, 1H), 8.37-8.27 (m, 1H), 8.04 (d, J=2.1Hz, 1H), 7.92-7.74 (m, 2H), 7.69 (dd, J=8.4, 3.0 Hz, 1H), 7.63-7.50 (m,2H), 7.50-7.28 (m, 4H), 6.92 (d, J=8.7 Hz, 1H) ppm.

Following a similar procedure as described above for compound (26), thefollowing compounds were prepared starting from2-fluoro-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide and thephenols listed below.

Cmpd. No. Product name Phenol 32 N-(3-sulfamoylphenyl)-2-(o-tolyloxy)-5-o-cresol (trifluoromethyl)benzamide 342-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)- 2-5-(trifluoromethyl)benzamide methoxyphenol 222-(4-methoxyphenoxy)-N-(3-sulfamoylphenyl)- 4-5-(trifluoromethyl)benzamide methoxyphenol 242-(4-chlorophenoxy)-N-(3-sulfamoylphenyl)-5- 4-(trifluoromethyl)benzamide Chlorophenol 6 2-(2,4-difluorophenoxy)-N-(3-2,4-di- sulfamoylphenyl)-5-(trifluoromethyl)benzamide fluorophenol 232-(4-ethoxyphenoxy)-N-(3-sulfamoylphenyl)-5- 4-(trifluoromethyl)benzamide ethoxyphenol 302-(4-chloro-2-methylphenoxy)-N-(3- 4-chloro-2-sulfamoylphenyl)-5-(trifluoromethyl)benzamide methylphenol 292-(3-fluoro-2-methoxyphenoxy)-N-(3- 3-fluoro-2-sulfamoylphenyl)-5-(trifluoromethyl)benzamide methoxyphenol 272-(4-fluoro-2-methoxyphenoxy)-N-(3- 4-fluoro-2-sulfamoylphenyl)-5-(trifluoromethyl)benzamide methoxyphenol 282-(3-fluoro-4-methoxyphenoxy)-N-(3- 3-fluoro-4-sulfamoylphenyl)-5-(trifluoromethyl)benzamide methoxyphenol 372-(4-isopropoxyphenoxy)-N-(3- 4-iso-sulfamoylphenyl)-5-(trifluoromethyl)benzamide propoxyphenol 362-(2,4-dimethoxyphenoxy)-N-(3- 2,4-di-sulfamoylphenyl)-5-(trifluoromethyl)benzamide methoxyphenol 352-(4-chloro-2-methoxyphenoxy)-N-(3- 4-chloro-2-sulfamoylphenyl)-5-(trifluoromethyl)benzamide methoxyphenol 312-(2-chloro-4-methoxyphenoxy)-N-(3- 2-chloro-4-sulfamoylphenyl)-5-(trifluoromethyl)benzamide methoxyphenol 412-(4-(difluoromethoxy)phenoxy)-N-(3- 4-(difluoro-sulfamoylphenyl)-5-(trifluoromethyl)benzamide methoxy)- phenol 39N-(3-sulfamoylphenyl)-2-(4- 4-(trifluoro- (trifluoromethoxy)phenoxy)-5-methoxy)- (trifluoromethyl)benzamide phenol

Example 29 Preparation of 5-fluoro-2-(4-fluoro-2methylphenoxy)-N-(3-sulfamoylphenyl)benzamide (21)

To a solution of 2,5-difluoro-N-(3-sulfamoylphenyl)benzamide (200 mg,0.64 mmol) in DMF (2 mL) was added 4-fluoro-2-methyl-phenol (72.99 μL,0.64 mmol) and cesium carbonate (1.0 g, 3.2 mmol) and the mixture washeated at 100° C. for 3 hours. The reaction was cooled to 25° C.,diluted with ethyl acetate and poured over water. The 2 layers wereseparated and the aqueous layer was extracted with ethyl acetate (2×).The organics were combined, dried over MgSO₄, filtered and evaporated toyield a red oil that was purified by column chromatography using agradient of ethyl acetate and hexanes to yield5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide(21) (7.2 mg, 3%).

Example 30 Preparation of4-cyano-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide(10)

To a solution of 4-cyano-2-fluoro-N-(3-sulfamoylphenyl)benzamide (19.2mg, 0.06 mmol) and 4-fluoro-2-methoxyphenol (42.6 mg, 0.3 mmol) in NMP(0.5 mL) was added Cs₂CO₃ (97.7 mg, 0.3 mmol) and the mixture wasstirred at 90° C. for 4 hours. The reaction was filtered and purified byreverse phase HPLC using a gradient of acetonitrile in water (1-99%) togive4-cyano-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-sulfamoylphenyl)benzamide.ESI-MS m/z calc. 441.08. found 442.3 (M+1)+; Retention time: 1.53minutes (3 minutes run).

Following a similar procedure as described above for compound (10), thefollowing compounds were prepared starting from4-cyano-2-fluoro-N-(3-sulfamoylphenyl)benzamide and the phenols listedbelow.

Cmpd No. Product name Phenol 4 2-(2-chloro-4-fluoro-phenoxy)-4-cyano-2-chloro-4- N-(3-sulfamoylphenyl)benzamide fluorophenol 94-cyano-2-(4-fluoro-2-methyl-phenoxy)- 4-fluoro-2-N-(3-sulfamoylphenyl)benzamide methyl-phenol

Example 31 Preparation of2-(2-chloro-4-fluorophenoxy)-5-cyano-N-(3-sulfamoylphenyl)benzamide (11)

To a solution of 5-cyano-2-fluoro-N-(3-sulfamoylphenyl)benzamide (31.9mg, 0.10 mmol) and 2-chloro-4-fluorophenol (44.0 mg, 0.30 mmol) in NMP(0.5 mL) was added Cs₂CO₃ (97.7 mg, 0.30 mmol) and the mixture wasstirred at 90° C. for 4 hours. The reaction was filtered and purified byreverse phase HPLC using a gradient of acetonitrile in water (1-99%)using HCl as a modifier to yield2-(2-chloro-4-fluoro-phenoxy)-5-cyano-N-(3-sulfamoylphenyl)benzamide(11) (5.8 mg, 13%). ESI-MS m/z calc. 445.03. found 446.1 (M+1)+;Retention time: 1.57 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6)δ 10.84 (s, 1H), 8.33 (s, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.92 (d, J=8.7Hz, 1H), 7.81 (d, J=6.9 Hz, 1H), 7.69 (dd, J=8.3, 2.8 Hz, 1H), 7.60-7.54(m, 2H), 7.48 (dd, J=9.1, 5.2 Hz, 1H), 7.44-7.34 (m, 3H), 6.88 (d, J=8.7Hz, 1H) ppm.

Example 32 Preparation of4-chloro-2-(4-fluorophenoxy)-5-methyl-N-(3-sulfamoylphenyl)benzamide (7)

To a solution of5-bromo-4-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide (122.3 mg, 0.3mmol) and 4-fluorophenol (100.9 mg, 0.9 mmol) in N,N-dimethylformamide(3 mL) was added cesium carbonate (293.2 mg, 0.9 mmol) and the reactionwas heated at 100° C. for 2 hours. The reaction was filtered andpurified by reverse phase preparative chromatography utilizing agradient of 20-99% acetonitrile in water containing HCl as a modifier toyield5-bromo-4-chloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide(59.5 mg, 40%).

To 5-bromo-4-chloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide(44 mg, 0.09 mmol), methylboronic acid (7.9 mg, 0.13 mmol),tetrakis(triphenylphosphine)palladium (0) (5.3 mg, 0.004 mmol) and1,2-dimethoxyethane (500 μL) was added sodium carbonate (132.1 μL of 2 Msolution, 0.26 mmol) and the reaction was heated at 80° C. for 65 hours.The reaction was filtered and the solvent was evaporated. The crudeproduct was purified by reverse phase LCMS using acetonitrile and watercontaining HCl as a modifier to yield4-chloro-2-(4-fluorophenoxy)-5-methyl-N-(3-sulfamoylphenyl)benzamide (7)(12.1 mg, 29%) as a yellow solid. ESI-MS m/z calc. 434.05. found 435.15(M+1)+; Retention time: 1.8 minutes (3 minutes run). ¹H NMR (400 MHz,DMSO-d₆) δ 10.65 (s, 1H), 8.30-8.24 (m, 1H), 7.81-7.72 (m, 1H), 7.68 (s,1H), 7.58-7.48 (m, 2H), 7.38 (s, 2H), 7.29-7.18 (m, 2H), 7.18-7.09 (m,2H), 6.98 (s, 1H), 2.36 (s, 3H) ppm.

Example 33 Preparation of4-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide (8)

To a solution of 4-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide (39.4mg, 0.12 mmol) and 2-chloro-4-fluorophenol (52.8 mg, 0.36 mmol) in DMF(0.8 mL) was added cesium carbonate (117.3 mg, 0.36 mmol) and thereaction was heated at 100° C. for 1 hour. The reaction was filtered andpurified by reverse phase preparative chromatography utilizing agradient of 10-99% acetonitrile in water containing HCl as a modifier toyield4-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide (8)(1.7 mg, 3%). ESI-MS m/z calc. 454.00. found 455.3 (M+1)⁺; Retentiontime: 1.73 minutes (3 minutes run).

Following a similar procedure as described above for compound (8), thefollowing compounds were prepared starting from4-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide and the phenols listedbelow.

Cmpd. No. Product name Phenol 154-chloro-2-(4-fluoro-2-methoxy-phenoxy)- 4-fluoro-2-N-(3-sulfamoylphenyl)benzamide methoxy-phenol 194-chloro-2-(4-fluoro-2-methyl-phenoxy)- 4-fluoro-2-N-(3-sulfamoylphenyl)benzamide methyl-phenol 844-chloro-2-(2,4-dimethoxyphenoxy)-N-(3- 2,4- sulfamoylphenyl)benzamidedimethoxyphenol 85 4-chloro-2-(4-chloro-2-methoxyphenoxy)- 4-chloro-2-N-(3-sulfamoylphenyl)benzamide methoxyphenol 864-chloro-2-(2-chloro-4-methoxyphenoxy)- 2-chloro-4-N-(3-sulfamoylphenyl)benzamide methoxyphenol 874-chloro-2-(4-isopropoxyphenoxy)-N-(3- 4- sulfamoylphenyl)benzamideisopropoxyphenol

Example 34 Preparation of2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide(40)

5-(Difluoromethyl)-2-fluoro-N-(3-sulfamoylphenyl)benzamide (75 mg, 0.22mmol), 2-chloro-4-fluoro-phenol (95.7 mg, 0.65 mmol) and cesiumcarbonate (212.9 mg, 0.65 mmol) in NMP (0.75 mL) was stirred at 90° C.for 2 hours. The reaction mixture was diluted with MeOH, filtered andpurification by reverse phase HPLC using a gradient of acetonitrile inwater (1-99%) and HCl as a modifier gave2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide(40) (56 mg, 53%) as a white solid. ESI-MS m/z calc. 470.03. found 471.3(M+1)⁺; Retention time: 1.63 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d₆) δ 10.77 (s, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 7.85-7.78 (m, 1H),7.72-7.64 (m, 2H), 7.60-7.53 (m, 2H), 7.39 (s br, 3H), 7.35 (d, J=8.1Hz, 1H), 7.10 (t, J=55.8 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H) ppm.

Example 35 Preparation of2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide(54)

To 2-fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide (75.7mg, 0.2 mmol), 4-fluoro-2-methoxyphenol (68.3 μl, 0.6 mmol), cesiumcarbonate (195.5 mg, 0.6 mmol) and N-methylpyrrolidinone (2 mL) wereadded and the reaction was stirred at 100° C. for 30 minutes to 2 hours.The reaction was filtered and mixture was purified by reverse phasepreparative chromatography utilizing a gradient of 10-99% acetonitrilein water containing HCl as a modifier to yield2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide(54) (27.8 mg, 27%). ESI-MS m/z calc. 500.07. found 501.2 (M+1)+;Retention time: 1.99 minutes (3 minutes run). ¹H-NMR (DMSO-d₆) δ 10.68(s, 1H), 8.37-8.30 (m, 1H), 7.84-7.79 (m, 1H), 7.77 (d, J=8.4 Hz, 1H),7.60-7.50 (m, 2H), 7.40 (s, 2H), 7.37-7.28 (m, 1H), 7.23-7.11 (m, 2H),6.93-6.82 (m, 1H), 6.58-6.50 (m, 1H), 3.75 (s, 3H) ppm.

The following compounds were prepared using a similar experimentalprocedure to compound (54) above starting from2-fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide and thephenols listed below.

Cmpd No. Product name Phenol 55 2-(4-fluorophenoxy)-N- 4-fluorophenol(3-sulfamoylphenyl)-4- (trifluoromethoxy)benzamide 562-(2-chloro-4-fluorophenoxy)-N-(3- 2-chloro- sulfamoylphenyl)-4-4-fluorophenol (trifluoromethoxy)benzamide 622-(2-chloro-4-methoxyphenoxy)-N-(3- 2-chloro-4- sulfamoylphenyl)-4-methoxyphenol (trifluoromethoxy)benzamide 63 2-(2-chlorophenoxy)-N-2-chlorophenol (3-sulfamoylphenyl)-4- (trifluoromethoxy)benzamide 642-(2-(difluoromethoxy)phenoxy)-N-(3- 2-(difluoro- sulfamoylphenyl)-4-methoxy)phenol (trifluoromethoxy)benzamide 652-(4-chloro-2-methoxyphenoxy)-N-(3- 4-chloro-2- sulfamoylphenyl)-4-methoxyphenol (trifluoromethoxy)benzamide 662-(3-chloro-2-methoxyphenoxy)-N-(3- 3-chloro-2- sulfamoylphenyl)-4-methoxyphenol (trifluoromethoxy)benzamide

Example 36 Preparation of2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide(70)

2-Fluoro-4-(1,1,2,2,2-pentafluoroethyl)-N-(3-sulfamoylphenyl)benzamide(34.2 mg, 0.1 mmol), the 2-methoxy-4-fluorophenol (34.2 μl, 0.3 mmol)and Cs₂CO₃ (97.8 mg, 0.3 mmol) in NMP (0.4 mL) was stirred at 80° C. for2 hours. Purification by HPLC using a gradient of 1-99% acetonitrile inwater, using HCl as a modifier, gave2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide(70) (17.8 mg, 33%). ESI-MS m/z calc. 534.07. found 535.3 (M+1)+;Retention time: 1.78 minutes (3 minutes run).

The following compounds were prepared using a similar experimentalprocedure as used for compound (70) above starting from2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)-N-(3-sulfamoylphenyl)benzamideand the phenols listed below.

Cmpd No. Product name Phenol 69 2-(4-fluorophenoxy)-4-(perfluoroethyl)-4-fluorophenol N-(3-sulfamoylphenyl)benzamide 712-(4-chloro-2-methoxyphenoxy)-4- 4-chloro-2- (perfluoroethyl)-N-(3-methoxyphenol sulfamoylphenyl)benzamide 722-(2-chloro-4-methoxyphenoxy)-4- 2-chloro-4- (perfluoroethyl)-N-(3-methoxyphenol sulfamoylphenyl)benzamide

Example 37 Preparation of4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide(77)

4,5-Dichloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide (50 mg, 0.14 mmol),4-fluoro-2-methoxyphenol (17.3 μl, 0.15 mmol), and K₂CO₃ (57.1 mg, 0.41mmol) were combined in DMF (0.5 mL) and heated at 75° C. for 12 hours.The reaction mixture was filtered and purified by reverse phase HPLCusing a gradient of acetonitrile in water 10-99% and 5 mM HCl in themobile phase to provide4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide(77) (7.5 mg, 11%). ESI-MS m/z calc. 484.01. found 485.3 (M+1)+;Retention time: 1.74 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6)δ 10.70 (s, 1H), 8.33-8.26 (m, 1H), 7.93 (s, 1H), 7.80 (dt, J=6.4, 2.3Hz, 1H), 7.60-7.49 (m, 2H), 7.40 (s, 2H), 7.29 (dd, J=8.8, 5.8 Hz, 1H),7.14 (dd, J=10.7, 2.9 Hz, 1H), 6.89-6.79 (m, 2H), 3.76 (s, 3H) ppm.

The following compounds were prepared using a similar experimentalprocedure as for compound (77) above starting from4,5-dichloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide and the phenolslisted below.

Cmpd No. Product name Phenol 76 4,5-dichloro-2-(2,4-dimethoxyphenoxy)-2,4- N-(3-sulfamoylphenyl)benzamide dimethoxyphenol 784,5-dichloro-2-(4-fluorophenoxy)-N-(3- 4-fluorophenolsulfamoylphenyl)benzamide 79 4,5-dichloro-2-(3-fluoro-4- 3-fluoro-4-methoxyphenoxy)-N- methoxyphenol (3-sulfamoylphenyl)benzamide 804,5-dichloro-2-(4-chloro-2- 4-chloro-2- methoxyphenoxy)-N- methoxyphenol(3-sulfamoylphenyl)benzamide 81 4,5-dichloro-2-(2-fluoro-4- 2-fluoro-4-methoxyphenoxy)-N- methoxyphenol (3-sulfamoylphenyl)benzamide 824,5-dichloro-2-(2-chloro-4- 2-chloro-4- methoxyphenoxy)-N- methoxyphenol(3-sulfamoylphenyl)benzamide 83 4,5-dichloro-2-(4-fluoro-2- 4-fluoro-2-methylphenoxy)-N-(3- methylphenol sulfamoylphenyl)benzamide

Example 38 Preparation of2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide(89)

To 2-Fluoro-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide (70mg, 0.16 mmol) and 4-fluoro-2-methoxyphenol (20.4 μL, 0.18 mmol) in DMF(68.4 μL) was added K₂CO₃ (67.5 mg, 0.49 mmol). The reaction was stirredat 70° C. for 2 hours, then at 100° C. for 1 hour. The reaction wascooled to room temperature, filtered and purified by reverse phase HPLCusing a gradient of acetonitrile in water (10-99%) to yield2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide(89) (44.9 mg, 50%). ESI-MS m/z calc. 552.06. found 553.2 (M+1)+;Retention time: 1.87 minutes (3 minutes run).

The following compounds were prepared using a similar experimentalprocedure as for compound (89) above starting from2-fluoro-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide and thephenols listed below.

Cmpd No. Product name Phenol 88 2-(4-fluorophenoxy)-N-(3- 4-sulfamoylphenyl)-4,6- fluorophenol bis(trifluoromethyl)benzamide 902-(3-fluoro-4-methoxyphenoxy)- 3-fluoro-4- N-(3-sulfamoylphenyl)-4,6-methoxyphenol bis(trifluoromethyl)benzamide 912-(2-fluoro-4-methoxyphenoxy)- 2-fluoro-4- N-(3-sulfamoylphenyl)-4,6-methoxyphenol bis(trifluoromethyl)benzamide 922-(5-fluoro-2-methoxyphenoxy)- 5-fluoro-2- N-(3-sulfamoylphenyl)-4,6-methoxyphenol bis(trifluoromethyl)benzamide 932-(4-fluoro-2-methylphenoxy)- 4-fluoro-2- N-(3-sulfamoylphenyl)-4,6-methylphenol bis(trifluoromethyl)benzamide

Example 39 Preparation of2,4-dichloro-6-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide(95)

A mixture of 2,4-dichloro-6-fluoro-N-(3-sulfamoylphenyl)benzamide (36.3mg, 0.1 mmol), 4-fluoro-2-methoxyphenol (34.2 μL, 0.30 mmol) and Cs₂CO₃(97.7 mg, 0.3 mmol) in NMP (0.4 mL) was stirred for 1 hour at 80° C. Thereaction mixture was diluted with methanol, filtered and purified byreverse phase HPLC using a gradient of acetonitrile/water (1-99%) andHCl as a modifier to give2,4-dichloro-6-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide(95) (6.5 mg, 13%) as a white solid. ESI-MS m/z calc. 484.01. found485.5 (M+1)+; Retention time: 1.58 minutes (3 minutes run). ¹H NMR (400MHz, DMSO-d6) δ 11.02 (s, 1H), 8.34 (s, 1H), 7.81-7.74 (m, 1H),7.61-7.53 (m, 2H), 7.48 (d, J=1.8 Hz, 1H), 7.41 (s, 2H), 7.21 (dd,J=8.8, 5.8 Hz, 1H), 7.15 (dd, J=10.6, 2.9 Hz, 1H), 6.89-6.81 (m, 1H),6.60 (d, J=1.8 Hz, 1H), 3.78 (s, 3H) ppm.

The following compounds were prepared using a similar experimentalprocedure as for compound (95) above starting from2,4-dichloro-6-fluoro-N-(3-sulfamoylphenyl)benzamide and the phenolslisted below.

Cmpd No. Product name Phenol 94 2,4-dichloro-6-(4-fluorophenoxy)-N-(3-4- sulfamoylphenyl)benzamide fluorophenol 96 2,4-dichloro-6-(4-fluoro-2-4-fluoro-2- methylphenoxy)- methylphenol N-(3-sulfamoylphenyl)benzamide97 2,4-dichloro-N-(3-sulfamoylphenyl)-6- 4-(trifluoro-(4-(trifluoromethoxy)phenoxy)benzamide methoxy)phenol 982,4-dichloro-6-(4-chloro-2- 4-chloro-2- methoxyphenoxy)- methoxyphenolN-(3-sulfamoylphenyl)benzamide 99 2,4-dichloro-6-(2-fluoro-4-2-fluoro-4- methoxyphenoxy)- methoxyphenolN-(3-sulfamoylphenyl)benzamide

Example 40 Preparation of2-cyclopropyl-6-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide(100)

To a mixture of2-cyclopropyl-6-fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide(20 mg, 0.08 mmol) and 3-fluoro-4-methoxyphenol (17.7 mg, 0.12 mmol) inDMF (0.5 mL) was added K₂CO₃ (41.2 mg, 0.3 mmol) and the reaction wasstirred at 100° C. for 2 hours, then at 80° C. overnight. The reactionwas cooled to room temperature, filtered and purified by reverse phaseHPLC using a gradient of acetonitrile in water (1-99%) and HCl as amodifier to yield2-cyclopropyl-6-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide(100) (3.69 mg, 9%). ESI-MS m/z calc. 524.10. found 525.2 (M+1)+;Retention time: 1.50 minutes (3 minutes run).

Example 41

Analytical data for the compounds of the present invention is providedbelow in Table 2. Mass Spec (e.g., M+1 data in Table 2), final purityand retention times were determined by reverse phase HPLC using aKinetix C18 column (50×2.1 mm, 1.7 μm particle) from Phenomenex (pn:00B-4475-AN)), and a dual gradient run from 1-99% mobile phase B over 3minutes. Mobile phase A=H₂O (0.05% CF₃CO₂H). Mobile phase B=CH₃CN (0.05%CF₃CO₂H). Flow rate=2 mL/min, injection volume=3 μL, and columntemperature=50° C.

TABLE 2 Analytical Data LCMS Reten- Cmpd. tion Time No in minutes(M + 1) ¹H-NMR (400 MHz) 1 1.96 455.3 (DMSO-d₆) δ 10.84 (s, 1H),8.34-8.24 (m, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.82-7.72 (m, 1H), 7.64(dd, J = 7.9, 0.8 Hz, 1H), 7.60-7.47 (m, 2H), 7.40 (s, 2H), 7.32-7.25(m, 2H), 7.25-7.18 (m, 2H), 7.15 (s, 1H) ppm. 2 1.95 473.2 3 1.86 455.5(DMSO-d₆) δ 10.81 (s, 1H), 8.30 (s, 1H), 8.01 (d, J = 2.3 Hz, 1H),7.86-7.78 (m, 2H), 7.59-7.53 (m, 2H), 7.39 (s, 2H), 7.35-7.24 (m, 4H),7.00 (d, J = 8.7 Hz, 1H) ppm. 4 1.57 446.3 5 1.71 421.1 6 1.91 473.3 71.8 435.15 (DMSO-d₆) δ 10.65 (s, 1H), 8.30-8.24 (m, 1H), 7.81-7.72 (m,1H), 7.68 (s, 1H), 7.58-7.48 (m, 2H), 7.38 (s, 2H), 7.29-7.18 (m, 2H),7.18-7.09 (m, 2H), 6.98 (s, 1H), 2.36 (s, 3H) ppm. 8 1.73 455.3 9 1.58426.3 10 1.53 442.3 11 1.57 446.1 (DMSO-d₆) δ 10.84 (s, 1H), 8.33 (s,1H), 8.20 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.81 (d, J =6.9 Hz, 1H), 7.69 (dd, J = 8.3, 2.8 Hz, 1H), 7.60- 7.54 (m, 2H), 7.48(dd, J = 9.1, 5.2 Hz, 1H), 7.44- 7.34 (m, 3H), 6.88 (d, J = 8.7 Hz, 1H)ppm. 12 1.66 469.3 13 1.61 485.3 (DMSO-d₆) δ 10.98 (s, 1H), 8.33 (s,1H), 7.79- 7.72 (m, 1H), 7.61-7.48 (m, 4H), 7.40 (s, 2H), 7.20 (dd, J =8.9, 5.9 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 Hz, 1H), 6.93 (d, J = 8.3 Hz,1H), 6.84 (td, J = 8.4, 2.8 Hz, 1H), 3.77 (s, 3H) ppm. 14 1.78 485.3 151.74 451.1 16 1.74 451.1 17 1.76 455.3 18 1.83 469.3 19 1.81 435.3 201.79 435.3 21 1.85 419.1 (DMSO-d₆) δ 10.73 (s, 1H), 8.30 (s, 1H), 7.75(m, 1H), 7.54 (m, 3H), 7.39 (s, 2H), 7.32 (m, 1H), 7.16 (dd, J = 9.4,2.9 Hz, 1H), 7.04 (td, J = 8.6, 3.2 Hz, 1H), 6.97 (dd, J = 8.8, 5.1 Hz,1H), 6.84 (dd, J = 9.1, 4.4 Hz, 1H), 2.18 (s, 3H) ppm. 22 1.76 467.2 231.85 481.1 24 1.82 471.2 25 1.81 469.2 (DMSO-d₆) δ 10.83 (s, 1H), 8.33(s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.81 (m, 2H), 7.56 (m, 2H), 7.40 (s,2H), 7.23 (ddd, J = 13.9, 9.1, 4.0 Hz, 2H), 7.14 (td, J = 8.6, 3.1 Hz,1H), 6.82 (d, J = 8.7 Hz, 1H), 2.15 (s, 3H) ppm. 26 1.78 489.2 (DMSO-d₆)δ 10.84 (s, 1H), 8.32 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 2.1 Hz, 1H),7.82 (m, 2H), 7.69 (dd, J = 8.4, 3.0 Hz, 1H), 7.56 (m, 2H), 7.47 (dd, J= 9.1, 5.3 Hz, 1H), 7.37 (m, 3H), 6.92 (d, J = 8.7 Hz, 1H) ppm. 27 1.79485.2 (DMSO-d₆) δ 10.74 (s, 1H), 8.33 (s, 1H), 7.97 (d, J = 2.2 Hz, 1H),7.84 (m, 1H), 7.77 (dd, J = 8.9, 2.2 Hz, 1H), 7.56 (m, 2H), 7.40 (s,2H), 7.35 (dd, J = 8.8, 5.9 Hz, 1H), 7.17 (dd, J = 10.7, 2.9 Hz, 1H),6.88 (td, J = 8.4, 2.9 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H)ppm. 28 1.73 485.2 29 1.74 485.1 30 1.9 485.2 31 1.81 501.1 32 2.0 451.1(DMSO-d₆) δ 10.82 (s, 1H), 8.32 (s, 1H), 8.01 (s, 1H), 7.81 (s, 2H),7.56 (s, 2H), 7.26 (m, 6H), 6.82 (d, J = 8.3 Hz, 1H), 2.15 (s, 3H) ppm.33 1.77 489.3 (DMSO-d₆) δ 11.02 (s, 1H), 8.32-8.25 (m, 1H), 7.73 (dt, J= 7.2, 2.0 Hz, 1H), 7.69-7.60 (m, 3H), 7.60-7.50 (m, 2H), 7.41 (s, 2H),7.37-7.31 (m, 2H), 7.13-7.07 (m, 1H) ppm. 34 1.72 467.1 (DMSO-d₆) δ10.74 (s, 1H), 8.33 (s, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.84 (m, 1H),7.77 (dd, J = 8.9, 2.3 Hz, 1H), 7.56 (m, 2H), 7.40 (s, 2H), 7.31 (dd, J= 11.5, 4.6 Hz, 2H), 7.23 (m, 1H), 7.05 (td, J = 7.7, 1.5 Hz, 1H), 6.78(d, J = 8.8 Hz, 1H), 3.74 (s, 3H) ppm. 35 1.82 501.1 (DMSO-d₆) δ 10.75(s, 1H), 8.32 (s, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.83 (dt, J = 6.2, 2.4Hz, 1H), 7.77 (dd, J = 8.9, 2.3 Hz, 1H), 7.56 (m, 2H), 7.40 (s, 2H),7.31 (dd, J = 5.4, 2.9 Hz, 2H), 7.11 (dd, J = 8.5, 2.4 Hz, 1H), 6.84 (d,J = 8.8 Hz, 1H), 3.77 (s, 3H) ppm. 36 1.75 497.1 37 1.88 495.1 38 1.72435.5 (DMSO-d₆) δ 10.83 (s, 1H), 8.41-8.36 (m, 1H), 7.76 (dt, J = 7.1,2.0 Hz, 1H), 7.63-7.51 (m, 3H), 7.39 (s, 2H), 7.34-7.25 (m, 3H),7.12-7.07 (m, 1H), 6.61 (t, J = 8.0 Hz, 1H), 2.35 (s, 3H) ppm. 39 2.16521.3 (DMSO-d₆) δ 10.83 (s, 1H), 8.31-8.23 (m, 1H), 8.05 (d, J = 2.3 Hz,1H), 7.87 (dd, J = 8.8, 2.2 Hz, 1H), 7.82-7.75 (m, 1H), 7.59-7.50 (m,2H), 7.50- 7.42 (m, 2H), 7.39 (s, 2H), 7.35-7.26 (m, 2H), 7.13 (d, J =8.8 Hz, 1H) ppm. 40 1.63 471.3 (DMSO-d₆) δ 10.77 (s, 1H), 8.32 (s, 1H),7.87 (s, 1H), 7.85-7.78 (m, 1H), 7.72-7.64 (m, 2H), 7.60- 7.53 (m, 2H),7.39 (s br, 3H), 7.35 (d, J = 8.1 Hz, 1H), 7.10 (t, J = 55.8 Hz, 1H),6.89 (d, J = 8.5 Hz, 1H) ppm. 41 2.06 503.2 (DMSO-d₆) δ 10.82 (s, 1H),8.33-8.26 (m, 1H), 8.03 (d, J = 2.3 Hz, 1H), 7.88-7.76 (m, 2H), 7.61-7.49 (m, 2H), 7.43-7.00 (m, 8H) ppm. 42 2.04 501.1 43 1.92 485.3(DMSO-d₆) δ ppm 10.82 (s, 1H), 8.35-8.25 (m, 1H), 7.87 (d, J = 7.9 Hz,1H), 7.82-7.73 (m, 1H), 7.62 (dd, J = 8.2, 1.6 Hz, 1H), 7.59-7.50 (m,2H), 7.40 (s, 2H), 7.31-7.10 (m, 3H), 7.06-6.94 (m, 1H), 3.83 (s, 3H)ppm. 44 1.94 467.2 45 2.01 481.3 46 2.1 495.4 47 1.98 451.2 48 2.0 501.249 2.0 481.3 50 1.97 497.4 51 2.08 521.4 (DMSO-d₆) δ 10.86 (s, 1H), 8.26(s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.78-7.68 (m, 2H), 7.60-7.49 (m, 2H),7.45-7.38 (m, 4H), 7.36 (s, 1H), 7.26-7.19 (m, 2H) ppm. 52 1.91 485.4 532.05 495.5 (DMSO-d₆) δ 10.82 (s, 1H), 8.36-8.28 (m, 1H), 7.85 (d, J =7.8 Hz, 1H), 7.83-7.76 (m, 1H), 7.61- 7.49 (m, 3H), 7.39 (s, 2H),7.17-7.08 (m, 2H), 7.07-6.93 (m, 3H), 4.65-4.50 (m, 1H), 1.25 (d, J =6.0 Hz, 6H) ppm. 54 1.99 501.2 (DMSO-d₆) δ 10.68 (s, 1H), 8.37-8.30 (m,1H), 7.84-7.79 (m, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.60- 7.50 (m, 2H),7.40 (s, 2H), 7.37-7.28 (m, 1H), 7.23-7.11 (m, 2H), 6.93-6.82 (m, 1H),6.58-6.50 (m, 1H), 3.75 (s, 3H) ppm. 55 1.96 471.3 (DMSO-d₆) δ 10.75 (s,1H), 8.32-8.28 (m, 1H), 7.84-7.74 (m, 2H), 7.59-7.49 (m, 2H), 7.39 (s,2H), 7.33-7.25 (m, 3H), 7.25-7.18 (m, 2H), 6.87- 6.79 (m, 1H) ppm. 562.0 505.2 (DMSO-d₆) δ 10.77 (s, 1H), 8.36-8.28 (m, 1H), 7.82 (d, J = 8.5Hz, 1H), 7.80-7.74 (m, 1H), 7.64 (dd, J = 8.4, 2.9 Hz, 1H), 7.59-7.48(m, 2H), 7.40 (s, 2H), 7.38-7.26 (m, 3H), 6.79 (d, J = 2.2 Hz, 1H) ppm.57 1.19 467 58 1.34 485 (DMSO-d₆) δ 11.03 (s, 1H), 8.29 (t, J = 1.8 Hz,1H), 7.72 (dt, J = 7.3, 2.0 Hz, 1H), 7.67-7.50 (m, 4H), 7.43 (d, J = 2.5Hz, 1H), 7.41 (s, 2H), 7.32 (dd, J = 8.6, 2.7 Hz, 1H), 7.12-7.04 (m,2H), 2.15 (s, 3H) ppm. 59 1.26 469 (DMSO-d₆) δ 11.05 (s, 1H), 8.29 (t, J= 1.8 Hz, 1H), 7.72 (dt, J = 7.3, 2.0 Hz, 1H), 7.68-7.50 (m, 4H), 7.41(s, 2H), 7.30 (td, J = 8.2, 6.5 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H),7.10-7.04 (m, 1H), 6.91 (d, J = 8.2 Hz, 1H), 2.08 (s, 3H) ppm. 60 1.36521 61 1.20 485 62 1.93 517.2 63 1.89 487.3 64 1.87 519.3 65 1.96 517.266 1.92 517.2 67 1.85 501.1 68 1.87 501.2 69 1.75 505.3 70 1.78 535.3(DMSO-d₆) δ 10.83 (s, 1H), 8.35 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H),7.84-7.77 (m, 1H), 7.62-7.49 (m, 3H), 7.40 (s, 2H), 7.32 (dd, J = 8.8,5.9 Hz, 1H), 7.16 (dd, J = 10.6, 2.8 Hz, 1H), 6.88 (ddd, J = 8.4, 2.8Hz, 1H), 6.76 (s, 1H), 3.73 (s, 3H) ppm. 71 1.84 551.3 72 1.79 551.1 731.83 471.3 (DMSO-d₆) δ 10.86 (s, 1H), 8.32-8.27 (m, 1H), 7.91 (d, J =7.9 Hz, 1H), 7.81-7.73 (m, 1H), 7.73- 7.65 (m, 1H), 7.61 (dd, J = 8.0,1.6 Hz, 1H), 7.58- 7.50 (m, 2H), 7.48-7.36 (m, 3H), 7.32-7.21 (m, 2H),7.10 (d, J = 1.6 Hz, 1H) ppm. 74 1.53 471.1 75 1.55 501.3 (CD₃OD) δ 8.31(t, J = 2.0 Hz, 1H), 7.79 (ddd, J = 8.1, 2.2, 1.1 Hz, 1H), 7.68 (dt, J =8.1, 1.3 Hz, 1H), 7.57-7.50 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.16 (d,J = 9.0 Hz, 1H), 7.09 (d, J = 2.9 Hz, 1H), 6.93 (dd, J = 9.1, 2.4 Hz,2H), 3.81 (s, 3H) ppm. 76 1.76 498.5 (DMSO-d₆) δ 10.67 (s, 1H), 8.31 (s,1H), 7.91 (s, 1H), 7.86-7.79 (m, 1H), 7.58-7.51 (m, 2H), 7.40 (s, 2H),7.21 (d, J = 8.8 Hz, 1H), 6.78-6.71 (m, 2H), 6.59 (dd, J = 8.9, 2.8 Hz,1H), 3.79 (s, 3H), 3.74 (s, 3H) ppm. 77 1.74 485.3 (DMSO-d₆) δ 10.70 (s,1H), 8.33-8.26 (m, 1H), 7.93 (s, 1H), 7.80 (dt, J = 6.4, 2.3 Hz, 1H),7.60- 7.49 (m, 2H), 7.40 (s, 2H), 7.29 (dd, J = 8.8, 5.8 Hz, 1H), 7.14(dd, J = 10.7, 2.9 Hz, 1H), 6.89-6.79 (m, 2H), 3.76 (s, 3H) ppm. 78 1.70455.5 (DMSO-d₆) δ 10.77 (s, 1H), 8.28-8.23 (m, 1H), 7.98 (s, 1H), 7.76(dt, J = 6.9, 2.1 Hz, 1H), 7.59- 7.49 (m, 2H), 7.39 (s, 2H), 7.26 (t, J= 8.7 Hz, 2H), 7.22-7.16 (m, 3H) ppm. 79 1.70 485.3 (DMSO-d₆) δ 10.74(s, 1H), 8.29-8.23 (m, 1H), 7.96 (s, 1H), 7.77 (dt, J = 7.0, 2.2 Hz,1H), 7.60- 7.50 (m, 2H), 7.40 (s, 2H), 7.25-7.14 (m, 3H), 6.97 (dt, J =9.4, 1.9 Hz, 1H), 3.83 (s, 3H) ppm. 80 1.82 503.1 (DMSO-d₆) δ 10.80 (s,1H), 8.32-8.28 (m, 1H), 7.96 (s, 1H), 7.80 (dt, J = 6.8, 2.2 Hz, 1H),7.59- 7.51 (m, 2H), 7.40 (s, 2H), 7.29 (t, J = 9.2 Hz, 1H), 7.06 (dd, J= 12.6, 2.9 Hz, 1H), 7.01 (s, 1H), 6.84 (ddd, J = 9.1, 3.0, 1.3 Hz, 1H),3.78 (s, 3H) ppm. 81 1.72 485.3 (DMSO-d₆) δ 10.80 (s, 1H), 8.32-8.28 (m,1H), 7.96 (s, 1H), 7.80 (dt, J = 6.8, 2.2 Hz, 1H), 7.61- 7.51 (m, 2H),7.40 (s, 2H), 7.29 (t, J = 9.2 Hz, 1H), 7.06 (dd, J = 12.6, 2.9 Hz, 1H),7.01 (s, 1H), 6.84 (ddd, J = 9.1, 3.0, 1.3 Hz, 1H), 3.78 (s, 3H) ppm. 821.8 501.3 (DMSO-d₆) δ 10.77 (s, 1H), 8.33-8.28 (m, 1H), 7.98 (s, 1H),7.79 (dt, J = 6.8, 2.2 Hz, 1H), 7.59- 7.51 (m, 2H), 7.40 (s, 2H), 7.32(d, J = 9.0 Hz, 1H), 7.20 (d, J = 3.0 Hz, 1H), 7.02 (dd, J = 9.0, 3.0Hz, 1H), 6.89 (s, 1H), 3.79 (s, 3H) ppm. 83 1.78 469.3 (DMSO-d₆) δ 10.78(s, 1H), 8.31-8.27 (m, 1H), 7.97 (s, 1H), 7.77 (dt, J = 7.0, 2.1 Hz,1H), 7.62- 7.50 (m, 2H), 7.40 (s, 2H), 7.21 (dd, J = 9.4, 2.9 Hz, 1H),7.15-7.04 (m, 2H), 6.95 (s, 1H), 2.17 (s, 3H) ppm. 84 1.65 463.3(DMSO-d₆) δ 10.55 (s, 1H), 8.32 (s, 1H), 7.82 (d, J = 3.5 Hz, 1H), 7.67(d, J = 8.2 Hz, 1H), 7.62-7.51 (m, 2H), 7.39 (s, 2H), 7.30-7.19 (m, 2H),6.76 (d, J = 2.7 Hz, 1H), 6.60 (dd, J = 8.8, 2.7 Hz, 1H), 6.56 (d, J =1.8 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H) ppm. 85 1.71 467.1 86 1.67 467.1(DMSO-d₆) δ 10.60 (s, 1H), 8.30 (s, 1H), 7.80 (s br, 1H), 7.68 (d, J =8.2 Hz, 1H), 7.63-7.50 (m, 2H), 7.39 (s, 2H), 7.32-7.20 (m, 3H),7.13-7.05 (m, 1H), 6.72 (d, J = 1.8 Hz, 1H), 3.77 (s, 3H) ppm. 87 1.76461.3 88 1.77 523.2 (DMSO-d₆) δ 11.16 (s, 1H), 8.25 (t, J = 1.8 Hz, 1H),7.99 (s, 1H), 7.72 (dt, J = 7.4, 1.9 Hz, 1H), 7.63-7.52 (m, 2H), 7.48(s, 1H), 7.43 (s, 2H), 7.37- 7.22 (m, 4H) ppm. 89 1.87 553.2 90 1.83553.2 91 1.87 553.23 92 1.85 553.23 93 1.93 537.2 94 1.57 455.3(DMSO-d₆) δ 11.06 (s, 1H), 8.30 (s, 1H), 7.77- 7.71 (m, 1H), 7.59-7.52(m, 3H), 7.41 (s, 2H), 7.29 (dd, J = 8.7 Hz, 2H), 7.25-7.19 (m, 2H),6.90 (d, J = 1.8 Hz, 1H) ppm. 95 1.58 485.5 (DMSO-d₆) δ 11.02 (s, 1H),8.34 (s, 1H), 7.81- 7.74 (m, 1H), 7.61-7.53 (m, 2H), 7.48 (d, J = 1.8Hz, 1H), 7.41 (s, 2H), 7.21 (dd, J = 8.8, 5.8 Hz, 1H), 7.15 (dd, J =10.6, 2.9 Hz, 1H), 6.89-6.81 (m, 1H), 6.60 (d, J = 1.8 Hz, 1H), 3.78 (s,3H) ppm. 96 1.64 469.3 97 1.73 521.3 98 1.68 501.3 99 1.58 485.5 100 1.5525.2

Example 42 Assays for Detecting and Measuring Na_(v) InhibitionProperties of Compounds

E-VIPR Optical Membrane Potential Assay Method with ElectricalStimulation

Sodium channels are voltage-dependent proteins that can be activated byinducing membrane voltage changes by applying electric fields. Theelectrical stimulation instrument and methods of use are described inIon Channel Assay Methods PCT/US01/21652, herein incorporated byreference and are referred to as E-VIPR. The instrument comprises amicrotiter plate handler, an optical system for exciting the coumarindye while simultaneously recording the coumarin and oxonol emissions, awaveform generator, a current- or voltage-controlled amplifier, and adevice for inserting electrodes in well. Under integrated computercontrol, this instrument passes user-programmed electrical stimulusprotocols to cells within the wells of the microtiter plate.

24 hours before the assay on E-VIPR, HEK cells expressing human Nav1.8were seeded in 384-well poly-lysine coated plates at 15,000-20,000 cellsper well. HEK cells were grown in media (exact composition is specificto each cell type and NaV subtype) supplemented with 10% FBS (FetalBovine Serum, qualified; GibcoBRL #16140-071) and 1% Pen-Strep(Penicillin-Streptomycin; GibcoBRL #15140-122). Cells were grown invented cap flasks, in 90% humidity and 5% CO₂.

Reagents and Solutions

-   -   100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO    -   Compound Plates: 384-well round bottom plate, e.g. Corning        384-well Polypropylene Round Bottom #3656    -   Cell Plates: 384-well tissue culture treated plate, e.g. Greiner        #781091-1B    -   10 mM DiSBAC₆(3) (Aurora #00-100-010) in dry DMSO    -   10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO    -   200 mM ABSC1 in H₂0

Bath1 buffer: Glucose 10 mM (1.8 g/L), Magnesium Chloride (Anhydrous), 1mM (0.095 g/L), Calcium Chloride, 2 mM (0.222 g/L), HEPES 10 mM (2.38g/L), Potassium Chloride, 4.5 mM (0.335 g/L), Sodium Chloride 160 mM(9.35 g/L).

Hexyl Dye Solution: Bath1 Buffer+0.5% β-cyclodextrin (make this prior touse, Sigma #C4767), 8 μM CC2-DMPE+2.5 μM DiSBAC₆(3). To make thesolution Added volume of 10% Pluronic F127 stock equal to volumes ofCC2-DMPE+DiSBAC₆(3). The order of preparation was first mix Pluronic andCC2-DMPE, then added DiSBAC₆(3) while vortexing, then addedBath1+β-Cyclodextrin.

Assay Protocol

1) Pre-spotted compounds (in neat DMSO) into compound plates. Vehiclecontrol (neat DMSO), the positive control (20 mM DMSO stock tetracaine,125 μM final in assay) and test compounds were added to each well at160× desired final concentration in neat DMSO. Final compound platevolume was 80 μL (80-fold intermediate dilution from 1 μL DMSO spot;160-fold final dilution after transfer to cell plate). Final DMSOconcentration for all wells in assay was 0.625%.

2) Prepared Hexyl Dye Solution.

3) Prepared cell plates. On the day of the assay, medium was aspiratedand cells were washed three times with 100 μL of Bath1 Solution,maintaining 25 μL residual volume in each well.

4) Dispensed 25 μL per well of Hexyl Dye Solution into cell plates.Incubated for 20-35 minutes at room temp or ambient conditions.

5) Dispensed 80 μL per well of Bath1 into compound plates. AcidYellow-17 (1 mM) was added and Potassium Chloride was altered from 4.5to 20 mM depending on the NaV subtype and assay sensitivity.

6) Washed cell plates three times with 100 μL per well of Bath1, leaving25 μL of residual volume. Then transferred 25 uL per well from CompoundPlates to Cell Plates. Incubated for 20-35 minutes at room temp/ambientcondition.

7) Read Plate on E-VIPR. Used the current-controlled amplifier todeliver stimulation wave pulses for 10 seconds and a scan rate of 200Hz. A pre-stimulus recording was performed for 0.5 seconds to obtain theun-stimulated intensities baseline. The stimulatory waveform wasfollowed by 0.5 seconds of post-stimulation recording to examine therelaxation to the resting state.

Data Analysis

Data was analyzed and reported as normalized ratios of emissionintensities measured in the 460 nm and 580 nm channels. The response asa function of time was reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{11mu}{nm}} - {background}_{460\mspace{11mu}{nm}}} \right)}{\left( {{intensity}_{580\mspace{11mu}{nm}} - {background}_{580\mspace{11mu}{nm}}} \right)}$

The data was further reduced by calculating the initial (R_(i)) andfinal (R_(f)) ratios. These were the average ratio values during part orall of the pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R=R_(f)/R_(i) was thencalculated and reported as a function of time.

Control responses were obtained by performing assays in the presence ofa compound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls werecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compound

Electrophysiology Assays for Na_(v) Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter)were visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modewas used to assess the compound's IC₅₀ holding the cells at −60 mV. Inaddition, the “current clamp” mode was employed to test the efficacy ofthe compounds in blocking action potential generation in response tocurrent injections. The results of these experiments contributed to thedefinition of the efficacy profile of the compounds.

The exemplified compounds in Table 1 herein are active against Nav1.8sodium channels as measured using the assays described herein and aspresented in Table 3 below.

TABLE 3 Nav1.8 IC₅₀ activity Cmpd. Nav1.8 IC₅₀ No (uM) 1 0.014 2 0.022 30.016 4 0.027 5 0.021 6 0.013 7 0.012 8 0.01 9 0.028 10 0.02 11 0.024 120.009 13 0.002 14 0.005 15 0.013 16 0.007 17 0.005 18 0.007 19 0.016 200.004 21 0.023 22 0.028 23 0.014 24 0.03 25 0.004 26 0.004 27 0.006 280.016 29 0.005 30 0.009 31 0.006 32 0.008 33 0.005 34 0.014 35 0.005 360.004 37 0.006 38 0.014 39 0.01 40 0.007 41 0.022 42 0.01 43 0.021 440.02 45 0.021 46 0.014 47 0.014 48 0.01 49 0.012 50 0.008 51 0.014 520.011 53 0.026 54 0.005 55 0.009 56 0.004 57 0.027 58 0.006 59 0.014 600.009 61 0.028 62 0.016 63 0.027 64 0.022 65 0.022 66 0.007 67 0.026 680.009 69 0.026 70 0.013 71 0.028 72 0.02 73 0.026 74 0.015 75 0.005 760.003 77 0.001 78 0.008 79 0.004 80 0.004 81 0.008 82 0.006 83 0.005 840.013 85 0.015 86 0.015 87 0.029 88 0.007 89 0.001 90 0.007 91 0.007 920.016 93 0.002 94 0.005 95 0.0009 96 0.001 97 0.004 98 0.0008 99 0.005100 0.018

Example 43

IonWorks Assays.

This assay was performed to determine the activity for the compounds ofthe present invention against non Na_(v)1.8 channels. Sodium currentswere recorded using the automated patch clamp system, IonWorks(Molecular Devices Corporation, Inc.). Cells expressing Na_(v) subtypeswere harvested from tissue culture and placed in suspension at 0.5-4million cells per mL Bath1. The IonWorks instrument measured changes insodium currents in response to applied voltage clamp similarly to thetraditional patch clamp assay, except in a 384-well format. Using theIonWorks, dose-response relationships were determined in voltage clampmode by depolarizing the cell from the experiment specific holdingpotential to a test potential of about 0 mV before and followingaddition of the test compound. The influence of the compound on currentswere measured at the test potential.

Example 44 Human Liver Microsome Assay Protocol

Liver microsomal stability data were generated as follows. Substrateswere incubated at 37° C. and shaken for 30 minutes in a phosphatebuffered solution with human liver microsomes and the cofactor NADPH. Atime zero control was similarly prepared, however with NADPH excluded.The final incubation concentrations were 1 uM substrate (0.2% DMSO), 0.5mg/mL liver microsome, 2 mM NADPH, and 0.1 M phosphate. Reactions werequenched and proteins precipitated with the addition of 2 volumeequivalents of ice cold acetonitrile containing an internal standard.Following a centrifugation step, aliquots from the quenched incubationswere further diluted with 4 volume equivalents of a 50% aqueous methanolsolution and then subjected to LC/MS/MS analysis for quantitation ofparent substrate. Microsome stability values were calculated as thepercent of substrate remaining after 30 minutes referenced against thetime zero control.

TABLE 4 Human liver microsome (HLM) data for selected compounds of thepresent invention is listed below. The values presented represent thepercent of compound remaining after 30 minutes using the protocoldescribed above in Example 44. Compounds with reported >100% percentunchanged after 30 minutes of incubation represent compounds that werenot metabolized under the assay conditions. The numbers exceeding 100%were due to variability in the analytical quantitation of the assay. Theabbreviation “ND”stands for no data. Cmpd. HLM: percent No. unchangedafter 30 min 1 83 2 97 3 117 4 118 5 107 6 106 7 78 8 108 9 102 10 86 1189 12 94 13 78 14 83 15 81 16 86 17 102 18 98 19 94 20 96 21 96 22 88 2375 24 102 25 94 26 119 27 101 28 92 29 100 30 103 31 82 32 76 33 102 3496 35 82 36 66 37 76 38 105 39 104 40 107 41 95 42 84 43 90 44 79 45 7246 67 47 100 48 68 49 57 50 72 51 89 52 81 53 71 54 96 55 95 56 102 5778 58 107 59 66 60 92 61 68 62 81 63 92 64 96 65 101 66 89 67 91 68 8069 110 70 87 71 81 72 67 73 95 74 102 75 62 76 58 77 95 78 104 79 91 80108 81 88 82 77 83 93 84 82 85 ND 86 82 87 ND 88 105 89 87 90 92 91 6992 113 93 96 94 97 95 91 96 96 97 102 98 62 99 63 100 ND

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art.

The specific embodiments described herein are offered by way of exampleonly.

We claim:
 1. A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence: R¹ is H, Cl, CH₃, CF₃ or cyclopropyl; R² is H, F,Cl, CN, CH₃, CF₃ or CHF₂; R³ is H, F, Cl, CN, CF₃, OCF₃ or CF₂CF₃; R⁴ isH; R⁵ is H, F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; R^(5′) is H,F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; R⁶ is H, F or Cl; R^(6′)is H, F or Cl; and R⁷ is H, F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ orOCHF₂, provided that R², and R³ are not simultaneously hydrogen; andthat R⁵, R^(5′), R⁶, R^(6′), and R⁷ are not simultaneously hydrogen. 2.The compound or salt according to claim 1, wherein R¹ is H, CF₃ or Cl;or R² is H, CF₃ or Cl; or R³ is H, CF₃, Cl or OCF₃; or R⁵ is H; or R⁶ orR^(6′) is H or F; or R⁷ is F, Cl, OCH₃ or OCF₃.
 3. The compound or saltaccording to claim 1, wherein R¹ is H or CF₃; or R² is H or CF₃; or R³is H, CF₃ or Cl; or R⁷ is F or OCH₃.
 4. The compound or salt accordingclaim 1, wherein the compound has formula I-D:

wherein, independently for each occurrence: R² is F, Cl, CN, CH₃, CF₃ orCHF₂; R⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; and R⁷ is F,Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.
 5. The compound or saltaccording to claim 4, wherein R² is Cl or CF₃; or R⁵ is F, Cl, CH₃ orOCH₃; or R⁷ is F, Cl, OCH₃ or OCF₃.
 6. The compound or salt according toclaim 1, wherein the compound has formula I-E:

wherein, independently for each occurrence: R³ is F, Cl, CN, CF₃, OCF₃or CF₂CF₃; R⁵ is F, Cl, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃ or OCHF₂; and R⁷is F, Cl, OCH₃, OCF₃, OCH₂CH₃, OCH(CH₃)₂ or OCHF₂.
 7. The compound orsalt according to claim 6, wherein R³ is Cl, CF₃ or OCF₃; or R⁵ is F,Cl, CH₃ or OCH₃; or R⁷ is F, Cl, OCH₃ or OCF₃.
 8. The compound or saltof claim 1, wherein the compound or a pharmaceutically acceptable saltthereof, is selected from the group consisting of:

2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide;

5-chloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

4-chloro-2-(4-fluorophenoxy)-5-methyl-N-(3-sulfamoylphenyl)benzamide;

4-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

4-cyano-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4-cyano-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-5-cyano-N-(3-sulfamoylphenyl)benzamide;

2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

4-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

2-(4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-ethoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-chlorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(3-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

N-(3-sulfamoylphenyl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-isopropoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-6-methyl-N-(3-sulfamoylphenyl)benzamide;

N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide;

2-(4-(difluoromethoxy)phenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(4-ethoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(2-propoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

N-(3-sulfamoylphenyl)-2-(o-tolyloxy)-4-(trifluoromethyl)benzamide;

2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(4-methoxy-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide;

2-(3-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(4-isopropoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(3-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)benzamide;

2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(2-(difluoromethoxy)phenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(3-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(3-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(3-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide;

2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide;

2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide;

2-(2-chloro-4-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide;

2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

4,5-dichloro-2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(2-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4-chloro-2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4-chloro-2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4-chloro-2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4-chloro-2-(4-isopropoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

2-(2-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

2-(5-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

2,4-dichloro-6-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

2,4-dichloro-6-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

2,4-dichloro-N-(3-sulfamoylphenyl)-6-(4-(trifluoromethoxy)phenoxy)benzamide;

2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

2,4-dichloro-6-(2-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;and

2-cyclopropyl-6-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;or a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound or a pharmaceutically acceptable salt thereof of claim 1 andone or more pharmaceutically acceptable carriers or vehicles.
 10. Amethod of inhibiting a voltage-gated sodium channel in a subjectcomprising administering to the subject a compound or a pharmaceuticallyacceptable salt thereof of claim
 1. 11. The method of claim 10, whereinthe voltage-gated sodium channel is Nav1.8.
 12. A method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiplesclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiacarrhythmia comprising administering an effective amount of a compound ora pharmaceutically acceptable salt thereof of claim
 1. 13. The method ofclaim 12, wherein the method comprises treating or lessening theseverity in a subject of gut pain, wherein gut pain comprisesinflammatory bowel disease pain, Crohn's disease pain or interstitialcystitis pain.
 14. The method of claim 12, wherein the method comprisestreating or lessening the severity in a subject of neuropathic pain,wherein neuropathic pain comprises post-herpetic neuralgia, diabeticneuralgia, painful HIV-associated sensory neuropathy, trigeminalneuralgia, burning mouth syndrome, post-amputation pain, phantom pain,painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapmentinjury, spinal stenosis, carpal tunnel syndrome, radicular pain,sciatica pain; nerve avulsion injury, brachial plexus avulsion injury;complex regional pain syndrome, drug therapy induced neuralgia, cancerchemotherapy induced neuralgia, anti-retroviral therapy inducedneuralgia; post spinal cord injury pain, idiopathic small-fiberneuropathy, idiopathic sensory neuropathy or trigeminal autonomiccephalalgia.
 15. The method of claim 12, wherein the method comprisestreating or lessening the severity in a subject of musculoskeletal pain,wherein musculoskeletal pain comprises osteoarthritis pain, back pain,cold pain, burn pain or dental pain.
 16. The method of claim 12, whereinthe method comprises treating or lessening the severity in a subject ofinflammatory pain, wherein inflammatory pain comprises rheumatoidarthritis pain or vulvodynia.
 17. The method of claim 12, wherein themethod comprises treating or lessening the severity in a subject ofidiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.18. The method according to claim 12, wherein said subject is treatedwith one or more additional therapeutic agents administered concurrentlywith, prior to, or subsequent to treatment with the compound, salt, orpharmaceutical composition.
 19. The method of according to claim 15,wherein the musculoskeletal pain comprises osteoarthritis pain.
 20. Apharmaceutical composition comprising the compound or a pharmaceuticallyacceptable salt thereof of claim 1 and one or more pharmaceuticallyacceptable carriers or vehicles.
 21. The method of claim 14, wherein theneuropathic pain comprises idiopathic small-fiber neuropathy.
 22. Themethod of claim 14, wherein the neuropathic pain comprises post-herpeticneuralgia.
 23. The method of claim 12, wherein the method comprisestreating or lessening the severity in a subject of acute pain, whereinthe acute pain comprises acute post-operative pain.
 24. The method ofclaim 12, wherein the method comprises treating or lessening theseverity in a subject of postsurgical pain.
 25. The compound of claim 1,wherein the compound is selected from the group consisting of:

2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide;

5-chloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

4-chloro-2-(4-fluorophenoxy)-5-methyl-N-(3-sulfamoylphenyl)benzamide;

4-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

4-cyano-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4-cyano-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-5-cyano-N-(3-sulfamoylphenyl)benzamide;

2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

4-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

2-(4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-ethoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-chlorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(3-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

N-(3-sulfamoylphenyl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-isopropoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-6-methyl-N-(3-sulfamoylphenyl)benzamide;

N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide;

2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide;

2-(4-(difluoromethoxy)phenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide;

2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(4-ethoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(2-propoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

N-(3-sulfamoylphenyl)-2-(o-tolyloxy)-4-(trifluoromethyl)benzamide;

2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(4-methoxy-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide;

2-(3-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(4-isopropoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(3-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)benzamide;

2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(2-(difluoromethoxy)phenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(3-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide;

2-(3-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(3-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide;

2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide;

2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide;

2-(2-chloro-4-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide;

2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide;

2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide;

4,5-dichloro-2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(2-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4,5-dichloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4-chloro-2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4-chloro-2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4-chloro-2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

4-chloro-2-(4-isopropoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

2-(2-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

2-(5-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide;

2,4-dichloro-6-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide;

2,4-dichloro-6-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide;

2,4-dichloro-N-(3-sulfamoylphenyl)-6-(4-(trifluoromethoxy)phenoxy)benzamide;

2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;

2,4-dichloro-6-(2-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide;and

2-cyclopropyl-6-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide.26. The pharmaceutical composition of claim 9, further comprising one ormore additional therapeutic agents.